It will be of little avail to the people that the laws are made by men of their own choice, if the laws be so voluminous that they cannot be read, or so incoherent that they cannot be understood; if they be repealed or revised before they are promulgated, or undergo such incessant changes that no man who knows what the law is today can guess what it will be tomorrow.

– Federalist No. 62, James Madison
February 27, 1788

Notwithstanding the above, we wish you all a very free and happy Fourth of July!

 

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FDA SAYS NO TO DRUG IMPORTS

The FDA recommends that U.S. Customs Service agents at mail-inspection sites be required to send back all small foreign drug shipments they find, said William Hubbard, senior associate commissioner at the FDA, in a House commerce oversight subcommittee meeting. The only exemption would be for “compassionate use,” where seriously ill patients order drugs from overseas that are not available in the U.S.

Although Congress authorized a rule allowing reimportation of prescription drugs by individuals in last year’s final budget reconciliation package (as a way to help individuals buy drugs at the reduced prices often available in other, poorer, countries), it is “looking doubtful” that such a regulation will be issued, according to Department of Health and Human Services Secretary Tommy G. Thompson. The FDA claims that such freedom cannot be allowed while the agency is unable to certify that the drugs coming back into the country are safe and are the same drugs that were exported. This is a fine excuse to protect their pharmaceutical company clients from price competition and to ensure the continued availability of six-figure-salary jobs at pharmaceutical companies for former FDA officials.

– The Wall Street Journal, June 8, 2001, p. B2
– Pharmaceutical & Medical Device Law Bulletin, April 2001, p.9

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REVIEW BY FDA COMMITTEE OF POTENTIAL TREATMENT FOR LUPUS

On April 19, 2001, the FDA’s Arthritis Advisory Committee considered data for a synthetic DHEA (dehydroepiandrosterone) product submitted by Genelabs Technologies (Redwood City, CA) as a treatment for systemic lupus erythematosus, a serious autoimmune condition for which there are few and limited treatments. The meeting largely pitted clinicians against an FDA statistical review that repeatedly characterized Genelabs’ data as “not statistically significant,” especially for adverse events when compared with placebo. The really odd (and fishy) thing about this meeting was that the FDA did not ask the Arthritis Advisory Committee to vote, thus avoiding a formal recommendation. This is considered highly unusual. We fear that this indicates the FDA will use any ploy to avoid approving DHEA for the treatment of any disease. The FDA well knows that DHEA is available as a dietary supplement and that the courts support First Amendment protection of the communication of truthful information about the effects of dietary supplements. Lost in the FDA’s calculations is the suffering of lupus victims.

– Nature Biotechnology 19:500 (2001)

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FDA THREATENS FOOD COMPANIES ON HERBS IN DRINKS

The FDA has sent warning letters to a number of manufacturers of popular soft drinks that contain herbs such as ginseng, gingko, and echinacea. Companies warned include US Mills, Inc., Hansen Beverage Co., and Fresh Samantha. The FDA demands that these companies prove that the herbs, which are “unapproved food additives” under current food (but not dietary supplement) law, are safe. New food-additive approvals usually cost $10 million to hundreds of millions of dollars and often take over a decade. Other companies selling herb-laced drinks, such as SoBe, will also face the same problem. These companies could avoid the “unapproved food additive” problem by relabeling their drinks as dietary supplements, but then they would have to list the amounts of the ingredients, including the herbs, that they contain. Customers would likely find out that the drinks contain very small and uncompetitive amounts of the herbal ingredients compared to other available dietary supplements.

– “New FDA Letters Warn Manufacturers of Tougher Stance on Herbal Additives,”
The Wall Street Journal, June 8, 2001

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HIGH CALCIUM INTAKE REDUCES MATERNAL BLOOD LEAD LEVELS

In pregnant women with low exposure to lead, high intakes of calcium (greater than 2000 mg/day) decreased the serum concentration of lead by inhibiting the breakdown of bone to release calcium for the fetus. Lead is accumulated over a lifetime and largely stored in bone. Hence, even a low exposure to lead can result in significant releases of lead during pregnancy unless inhibited by, for example, a high calcium intake. Moreover, calcium blocks the intestinal absorption of lead. The calcium supplement in this study¹ was twice the amount of calcium recommended for women during pregnancy and approached the upper level for calcium of 2500 mg/day.

A total of 753 women were enrolled initially, with a final sample of 195 women selected for lead determinations. The final group was selected so as to maintain an equal number of African-American and white women and to oversample women with low (less than 1000 mg/day) and high (over 2000mg/day) intakes of calcium. Calcium intake was estimated by food frequency questionnaires, as well as evaluation of calcium from prenatal vitamins, calcium supplements, and calcium-containing antacids. The results showed that higher calcium intake was associated with lower blood lead concentrations from week 20 to the end of pregnancy. The findings also suggested that relatively high intakes of calcium (over 2000 mg/day) may be needed to obtain the maximum blunting of the rise in blood lead during pregnancy.

Reference

1. Johnson, “High Calcium Intake Blunts Pregnancy-Induced Increases in Maternal Blood Lead,” Nutrition Reviews 59(5):152-156 (2001).

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HIGH PROLACTIN LEVELS MAY PROMOTE PROSTATE CANCER

Dysplasia, a pretumor lesion, develops in the prostates of rats treated for 16 weeks with a combined regimen of testosterone and estradiol. (Some testosterone is naturally converted to estradiol by the enzyme aromatase.) This regimen also increases prolactin levels in the blood. However, bromocriptine (Parlodel^®) effectively inhibited the evolution of tumors (six out of eight rats) and the often associated inflammation (five out of eight rats) in most of the animals. These data extend the many previous studies that have detailed marked influences of pituitary prolactin release on rat prostatic functions. However, the current study is the first to implicate pituitary prolactin release in prostatic pretumors.

Carcinogenesis 18(8):1505-1510 (1997), as reported in the July 1998 Life Extension magazine

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BROMOCRIPTINE SUPPRESSES PROLACTIN

The two of us have been taking bromocriptine (our current dose is 2.5 mg total per day, taken in two divided doses) for over 25 years for its antioxidant and dopaminergic neuron-protective effects, as well as its prolactin-suppressing effects (see p. 766 of our best-selling 1982 book, Life Extension, a Practical Scientific Approach, for Durk’s use for a problem of long-time hyperprolactinemia). As we noted in the book (p. 339), bromocriptine has been shown in animal studies to suppress the development of breast cancer after exposure to DMBA, a polynuclear aromatic hydrocarbon combustion tar. Also, on p. 190, we note that excess prolactin can be a contributing cause of prostate enlargement.

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HIGH PROLACTIN LEVELS MAY DAMAGE ENDOTHELIAL CELLS

It is known that prolactin levels increase in response to stress. A new study¹ examined the effects of elevated (but still physiological) concentrations of prolactin (PRL) on the responses of cultured endothelial cells after mechanical injury to cell monolayers. The authors report that, when treated at the time of injury with PRL levels of 62.5-1000 ng/mL, cells at the wound front became abnormal in shape and reductions in f-actin staining in comparison to controls that were not PRL-treated. High PRL concentrations also inhibited the adhesion of cells to their growth surface in a dose-dependent manner. Thus, the authors propose that these novel effects of PRL may be mediated by activation of an endothelial-cell PRL receptor. The results also suggest that high prolactin levels, such as might occur during prolonged and/or frequent stress, use of high-dose anabolic steroids, or the higher prolactin levels seen in aging, might contribute to endothelial cell damage and hence increase the risk of cardiovascular disease.

Reference

1. Merkle et al., “Structural and Functional Effects of High Prolactin Levels on Injured Endothelial Cells,” Endocrine 13(1):37-46 (2000).

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HEART-RATE VARIABILITY CORRELATED WITH N-3 FATTY ACIDS

Reduced heart-rate variability (HRV) is a predictor of arrhythmia and sudden cardiac death and is also known to be associated with age. A recent Danish study has found dietary intake of n-3 fatty acids and wine to be correlated with HRV. (However, after controlling for n-3 fatty acids, the correlation between wine and HRV was no longer significant. Apparently, at least in these Danish subjects, those who consumed high levels of fish were likely also to drink higher levels of wine.) Additional research¹ on the patients in that study verified the patients’ dietary intake of n-3 fatty acids (through consumption of fish) by measuring the n-3 fatty acid composition of the patients’ blood granulocyte membranes and adipose (fat) tissue. The researchers found the level of docosahexaenoic acid (DHA) in granulocytes had the highest correlation with HRV.

The accompanying editorial by J. Thomas Bigger, Jr., and Terek El-Sherif stated that “The details of the antiarrhythmic action for n-3 PUFA [polyunsaturated fatty acids] remain to be elucidated . . . but the overall body of evidence from epidemiological studies and two clinical trials suggests that n-3 PUFA have an important antiarrhythmic effect in patients with coronary heart disease. Unfortunately, coronary heart disease is often announced by sudden cardiac death. Given the safety and low cost of implementing a recommendation for a modest amount of fish in the diet, adequate dietary fish intake has a significant role to play in the primary and secondary prevention of out-of-hospital sudden cardiac death.”

The American Heart Association, publisher of Circulation, now recommends increased fish consumption to at least two fish servings per week. Their latest recommendation notes that “Because of the beneficial effects of n-3 fatty acids on risk of coronary artery disease as well as other diseases such as inflammatory and autoimmune diseases, the current intake, which is generally low, should be increased.”

– Inform, June 2001, p. 619*

*Inform is published by the American Oil Chemists Society as a source of international news on research and development of fats, oils, and related materials.

Reference

1. Circulation 103:651-657 (2001), as reported in Inform, June 2001, p. 618.

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LIFE EXTENSION WITH FATTY FISH

Dariush Mozaffarian of the University of Washington Veterans Affairs Medical Center in Seattle, Washington, reported at the 41st Annual Conference on Cardiovascular Disease Epidemiology and Prevention in San Antonio, Texas, that, in a study group of average age 72 years, eating fatty fish (such as tuna, salmon, and mackerel, but not fried lean fish, such as cod and snapper) at least once a week was found to lead to a  44% lower risk of dying from a heart attack.

– Inform, May 2001, p. 500

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FATTY FISH CONSUMPTION AND RISK OF PROSTATE CANCER

A new paper published in The Lancet¹ reports an epidemiological study of 6272 Swedish men followed for 30 years. They found that the men who ate no fish had a two-fold to three-fold higher frequency of prostate cancer than did those who ate moderate or high amounts. The authors propose that “. . . fish consumption could be associated with decreased risk of prostate cancer.” One of the n-3 fatty acids, eicosapentaenoic acid (EPA), competes with arachidonic acid as a substrate for cyclooxygenases and can therefore have an important effect on the formation of tumor-growth-enhancing prostaglandins.

Reference

1. Terry et al., “Fatty Fish Consumption and Risk of Prostate Cancer,” The Lancet 357:1764-1766 (2001).

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GREAT NEWS FOR PEOPLE WHO HATE FISH!
DURK & SANDY’S NEW HIGH-PROTEIN, HIGH-WHOLE-GRAIN RYE PANCAKES NOW CONTAIN N-3 FATTY ACIDS

n-3 PUFAs (polyunsaturated fatty acids) are offered by Hoffmann-LaRoche in a highly purified powdered form that has no fishy taste or smell, even in pancakes – not even if you burp after eating the pancakes. We have added to each serving of our pancakes (about three pancakes) a similar amount of n-3 fatty acids to what you would get in one meal of fatty fish. So if you hate fish, you don’t have to eat it; you can get your n-3 fatty acids in delicious and healthful pancakes instead. Each serving contains not only the n-3 fatty acids, but 17 grams of protein (from 90% whey protein), 3 grams of fiber, and whole-grain rye flour, which contains lignans (phytoestrogens) converted by intestinal bacteria to enterolactone and other mammalian lignans that may protect against chronic disease.¹

Reference

1. See, e.g., Venharanta et al., “Risk of Acute Coronary Events According to Serum Concentrations of Enterolactone,” The Lancet 354:2112-2115 (1999); Rickard and Thompson, “Phytoestrogens and Lignans: Effects on Reproduction and Chronic Disease,” Chapter 16 of Antinutrients and Phytochemicals in Food, ed. by Fereidoon Shahidi, ACS Symposium Series 662, 1997; [Rye and soy vs. prostate cancer], Prostate 42(4):304-314 (2000); Grasten et al.,”Rye Bread Improves Bowel Function and Decreases the Concentrations of Some Compounds that Are Putative Colon Cancer Risk Markers in Middle-Aged Women and Men,” J Nutr 130:2215-2221 (2000).

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PAIN-FREE SKIN TEST FOR CHOLESTEROL

A Canadian company, International Medical Innovations, Inc., of Toronto, has released information on a new product for measuring cholesterol level that does away with the need for a blood sample and painful lancets. The procedure takes three minutes and reads a color change in a drop of liquid on the palm of the hand using a hand-held spectrophotometer. Skin cholesterol, the firm said, correlates strongly with angiographically proven coronary artery disease and thus may be a superior assessment measurement than blood cholesterol. The test has received a medical device license from Health Canada for sale in Canada, and a submission to the FDA is anticipated. A home version of the test is being developed (see www.imin.ca).

– Inform, May 2001, pp. 500-501

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CONSENSUS PANEL RECOMMENDS MODERATE ALCOHOL CONSUMPTION

At a scientific meeting organized by the New York Academy of Sciences (Alcohol and Wine in Health and Disease, April 26-29, 2001, in Palo Alto, CA), a consensus statement is now cautiously recommending moderate consumption of alcohol. “If you drink, do so with moderation. But if you do not drink, ask your doctor. Moderate alcohol consumption at meals may be advisable.” Prior to this, the recommendation on alcohol was “If you don’t drink, don’t start.” Participants at this meeting agreed that efforts to prevent alcohol abuse should continue but that there should be no effort to induce moderate drinkers to quit. Curtis Ellison (Boston University, MA) noted that even if 5% of current abstainers became abusers, there would still be a net public health benefit from alcohol consumption.

– Gaetano, Simini, “Drink in Moderation, Says Consensus Panel,” The Lancet 357:1511 (2001)

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NEW CHOLESTEROL RECOMMENDATIONS MAY INCREASE STATIN DRUG SALES BY BILLIONS

The National Cholesterol Education Program (NCEP), a federal government health panel, recently issued new clinical guidelines establishing “healthy” levels of cholesterol (LDL and HDL) and for reducing excessively high LDL levels. Because of the reduction in the acceptable levels of total and LDL cholesterol, the sales of the popular cholesterol-lowering statin drugs may grow by up to $10 billion a year in the U.S. over the next four years. The number of Americans taking prescription drugs to lower their cholesterol could triple from the current 13,000,000.

In 2000, sales of cholesterol reducers in the U.S. were over $9 billion, including $4.1 billion for Pfizer’s Lipitor (atorvastatin) and $2.8 billion for Merck’s Zocor (simvastatin). The statins represent about 90% of the cholesterol-lowering drug market.¹ The upcoming production of generic versions of older statins, such as Merck’s Mevacor (lovastatin), now a minor drug in the statin market due to the advent of more effective statins, could result in a large usage of statins among those who cannot now afford them.

Strangely, there appears to have been no mention of niacin, which only a few years ago was called by the FDA the “drug of choice” for cholesterol reduction. Niacin is very effective at lowering LDL, VLDL, and triglycerides and also greatly increases HDL. Long-term studies have shown reductions in disease progression and mortality in subjects with cardiovascular disease. Nicotinic acid (but not nicotinamide) in gram doses is reported in the PDR Generics (first edition, p. 2035) to produce an average 10-20%reduction in total and LDL-cholesterol, a 30-70% reduction in triglycerides, and an average 20-35% increase in HDL-cholesterol. In a 1999 review,² niacin was said to have greater ability to increase HDL than any other drug. Perhaps the fact that there is not a lot of money to be made selling niacin, especially as it is a dietary supplement offered in a highly competitive market, has something to do with this focus on statins. Nobody is spending large sums of money promoting niacin or conducting large double-blind studies with it. Then, of course, there is the harmless flushing caused by niacin that some people apparently do not like. (Perhaps those people would change their minds about the flush if they were to try taking niacin during sex; histamine release is required for orgasm, and the niacin flush is caused by histamine release.)

It is true that some people’s livers cannot handle doses above about 800 mg a day, and it can be a problem for those with peptic ulcer. Liver tests should be done before niacin use and after to ensure that any possible liver problem is detected early. The PDR Generics notes (first edition, p. 2036), “Great caution must be exercised when Niacin is used in patients with coronary disease or gallbladder disease. Patients with a past history of jaundice, hepatobiliary disease, or peptic ulcer should be observed closely during Nicotinic Acid therapy. Frequent monitoring of liver function tests and blood glucose should be performed to ascertain that the drug is producing no adverse effects on these organ systems. Diabetic patients may experience a dose-related rise in glucose intolerance, the clinical significance of which is unclear.” A recent study³reported that while niacin use increased blood glucose levels modestly by 8.7 and 6.3 mg/dL for participants with and without diabetes, respectively, it also increased HDL by 29% and 29% and decreased triglycerides by 23% and 28% and LDL by 8% and 9%, respectively. Two of 125 diabetic patients and three of 363 nondiabetic patients, all of whom were on niacin, had elevated plasma alanine aminotransferase, a liver enzyme.

There are additional warnings for interactions between niacin and certain drugs. It should also be noted that sustained-release versions of niacin have been found to be associated with more adverse side effects than ordinary-release niacin. We recommend not using sustained-release niacin.

But statins also have adverse reactions and side effects. In the warnings for Lipitor and Zocor, for example, it is noted that the drug may cause liver-function abnormalities or myopathy (muscle aches or weakness) in conjunction with elevated levels of creatine phosphokinase (CPK) values. About 1% of patients are reported in the 1999 PDR to have persistently elevated liver enzymes with Zocor. Read the long discussions of possible side effects for statins in the PDR.

Another possible treatment could be small doses of a statin plus another cholesterol-reducing drug, food, or nutrient. (When using a statin with another drug, be sure to check the PDR for potential adverse interactions.) In one recent study, treatment with simvastatin at 12 mg/day and niacin at 3.2 g/day given to 80 of 160 subjects resulted in nearly a 70% reduction in the incidence of death, nonfatal myocardial infarction, stroke, and hospitalization for cardiovascular disease during a three-year followup.⁴ In that study, only one of 80 subjects withdrew from niacin because of flushing, while a few patients had their niacin dosage reduced due to increased liver transaminase levels. The usual starting dose for simvastatin is 20 mg, with pills available at doses of 5, 10, 20, and 40 mg.

n-3 (Omega-3) Fatty Acids are Very Effective at Reducing High Triglycerides
A surprisingly effective way to increase low HDL is moderate alcohol consumption. Recent results of the effects of moderate alcohol consumption on cardiovascular risk for diabetics, who are at unusually high risk for heart attack and other vascular problems, reported exceptional protection. For example, in a study⁵ involving 5103 type 2 diabetic women from the Nurses’ Health Study, the age-adjusted risk ratio for coronary heart disease for those who reported a usual alcohol intake of 0.1 to 4.9 g of alcohol per day was 0.74, and the risk ratio for women reporting a usual daily alcohol intake greater than or equal to 5 g per day was 0.48. This inverse relationship remained significant even after multivariate analysis adjusting for multiple other cardiovascular risk factors. (Though there was apparently no adjustment for n-3 fatty acids, we do not know whether these American women, like the Danish subjects in the study mentioned above, also tended to eat more fish if they drank more alcohol. It seems unlikely to us, but that is just a guess.) A recent paper⁶ also reports that, in a study sample of 2006 men and women aged 18-88 participating in a national health survey carried out in former West Germany in 1987-1988, nondrinkers and heavy drinkers had higher C-reactive protein than moderate drinkers. C-reactive protein is a marker of inflammation and also of coronary heart disease risk.

We are not against the use of statins, which appear to be effective in reducing cholesterol and may have other useful effects. However, it appears to us that the conclusion of the NECP that people who cannot reduce cholesterol with diet and exercise should then take expensive statins is not an adequate analysis of the available options, and yet this advice stands to be of immense profit to a very small number of companies.

References

1. Jarvis, “New Cholesterol Study Could Boost Statin Sales,” Chemical Marketing Reporter, June 11, 2001, p. 7.

2. Knopp, “Drug Treatment of Lipid Disorders,” New England Journal of Medicine, Aug. 12, 1999, p. 504.

3. Elam et al., “Effect of Niacin on Lipid and Lipoprotein Levels and Glycemic Control in Patients with Diabetes and Peripheral Arterial Disease,” Journal of the American Medical Association 284(10):1263-1270 (2000).

4. Zoler, “Niacin Plus Statin Cuts Coronary Events by 70%,” Family Practice News, January 1, 2001, as reported in Clinical Pearls News, June 2001, p. 101.

5. Solomon et al., “Moderate Alcohol Consumption and Risk of Coronary Heart Disease Among Women with Type 2 Diabetes Mellitus,” Circulation 102:494-499(2000).

6. Imhof et al., “Effect of Alcohol Consumption on Systemic Markers of Inflammation,” The Lancet 357:763-767 (2001).

From Special Politically Incorrect Issue

Allowing government officials to access a private person’s medical records without a warrant is a violation of the Fourth Amendment to the United States Constitution, which protects American citizens from warrantless searches by government officials.

– Rep. Ron Paul, R-TX

Wherever the real power in a Government lies, there is the danger of oppression. In our Governments the real power lies in the majority of the Community, and the invasion of private rights is chiefly to be apprehended, not from acts of Government contrary to the sense of its constituents, but from acts in which the Government is the mere instrument of the major number of the constituents.

– James Madison, letter to Thomas Jefferson, October 17, 1788

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WHY DRUGS COST LESS IN CANADA – OR DO THEY?

There has been a great deal of misinformation floating about on the subject of why some drugs are less expensive in Canada. This has led some to propose that a system of government drug-price controls would be a good way to reduce drug costs here.

A recent paper in Regulation, a journal on the economic effects of regulations,¹ makes some very interesting points in a comparison of the availability and cost of drugs in Canada and the U.S. It is not government price controls that make patented drugs cheaper in Canada, but the far lower standard of living of Canadians compared to Americans. At the same time, generic drugs cost more in Canada than the U.S.

Countries with Higher Incomes Generally Have Higher Drug Prices
A study conducted by one of the authors of this paper (along with a colleague)² compared American and Canadian wholesale and retail drug prices for the 60 most-prescribed drugs in the U.S. and found that the average retail price for generics was higher in Canada than in the U.S., while branded drugs were significantly cheaper in Canada. A graph in the Regulation paper showed that countries with higher incomes generally have higher drug prices. Since the founding of the Canadian Patented Medicine Prices Review Board (PMPRB), a federal quasi-judicial body that regulates introductory prices of newly patented drugs and price increases of extant patented drugs, the median Canadian price for patented drugs has declined relative to other developed countries, but Canada’s gross domestic product per capita (which reflects individual income) has also declined relative to those countries. The relative decline in Canadian living standards has been a factor leading to relatively low price increases for patented drugs versus other countries. In fact the 19% widening of the gap between Canadian and American aggregate price levels between 1987 and 1998 explained all but 5% of the increase in the pharmaceutical price difference between the two countries.

Effects of Legal Liability 
When you consider the fact that the U.S. is a more litigious society than Canada, you would expect that American pharmaceutical prices would be higher (than they otherwise would be) because of those higher costs of legal liability. This accounts for some of the patented-drug price differences between the U.S. and Canada.

Competitive Markets Tend to Reduce Prices for Generics
Generic drugs are more expensive in Canada than the U.S. Given lower incomes and less tort litigation in Canada, one would expect Canadian prices to be lower, but they aren’t. The reason for this is that the American generic market is more competitive than is the Canadian. In 1992, America had an average of 5.7 manufacturers of each therapeutic molecule, while Canada had only 2.02 (i.e., one branded and one generic firm). Moreover, there is much greater concentration in the generic drug industry in Canada. Of the ten top-selling pharmaceutical companies in Canada, only one is a generic manufacturer; the second-largest generic ranks thirteenth. These two generic firms together had fully 71% of the total generic market by revenue. Because Canada’s drug-pricing regime discourages producers of branded drugs from ever lowering their prices, generic drugs can be marketed with a much smaller discount than is the case for generics in the U.S.

Conclusion: There is no free lunch. Government regulation of drug prices in the United States would make drugs cheaper if you could get them (i.e., supplies of the drugs whose prices were kept below the U.S. free-market price would fall). Moreover, the investment in research and development that currently makes the United States the world leader in developing new prescription drugs would fall. Government price controls on drugs (or anything else) are a bad idea that visibly benefits some (such as politicians buying votes and those looking for a free lunch at somebody else’s expense) at the less visible expense of everybody else (e.g., dead body #9,287,604 died while on the waiting list to get price-controlled cheap drugs).

References

1. Robert R. Graham, “Seeing Through the Snow,” Regulation, Spring 2001, pp. 46-49.
2. Graham and Robson, “Prescription Drug Prices in Canada and the United States – Part 1: A Comparative Survey,” Public Policy Source Number 42, The Fraser Institute, 2000.

 

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WEEDS MAY BE UNRECOGNIZED GOLD MINE FOR NEW MEDICINES

According to a new study reported in The Lancet,¹ a better place than rain forests to look for new medicinals may be the weeds found in vacant lots. The reason, they propose, is that fast-growing weeds are more likely than rain-forest plants to rely upon chemical warfare (rather than other protection such as thick bark, woody stems, or thick leaves) to fight off predators and hence are more likely to produce compounds such as alkaloids, glycosides, and flavonoids that have pharmacological effects. The researchers studied medicinal plant use of 208 residents in six communities of the highlands of Chiapas, Mexico, where 80% of the people speak only the Mayan language of Tzeltal. Over a 7-month period, the villagers collected 103 different plant species for medical uses, mostly respiratory and gastrointestinal disorders. Thirty-five of the 103 plants used were weeds, defined as fast-growing species that thrive in areas that have been disturbed by human activities, such as land clearing and trail making. The weeds used by the villagers as medicines comprised about a third of their medicinal plants, when only 13% of the plants in the area are classified as weeds.

Reference

1. Stepp and Moerman, J Ethnopharmacol 75:19-23 (2001), as reported in McCarthy, “Weeds, not jungle plants, are more likely to have medicinal value,” The Lancet 357:938 (2001).

 

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VITAMIN E MAY REDUCE THE RISK OF ATHEROSCLEROSIS

The above is politically incorrect only for the FDA and its “public interest” minions. As you may know, the FDA recently denied our application for a health claim (initially filed in 1994) that vitamin E may reduce the risk of cardiovascular disease, despite the large body of scientific literature supporting the claim. The FDA continues to require the same standards to support dietary supplement health claims – large, multiyear, expensive, double-blind, placebo-controlled human trials – despite the explicit instructions from the Congress in the 1991 Nutrition Labeling and Education Act and the 1994 Dietary Supplement Health and Education Act that provide that consumers should have access to information about dietary supplements before the degree of “certainty” required of prescription drugs has been reached.¹

Despite the FDA’s pronouncements, however, the body of evidence supporting a protective role for vitamin E continues to accumulate. A new study² uncovers what may be an important mechanism for part of vitamin E’s protective effects in atherosclerosis: reduced expression of CD36 SR.

Epidemiological studies have associated increased levels of low-density lipoproteins with an increased risk of atherosclerosis. The mechanism is still unclear. Although intracellular cholesterol provides feedback inhibition so that cholesterol accumulation does not continue unimpeded, oxidized LDL and other forms of modified LDL (e.g., acetylated LDL) do not provide such feedback. Hence, these forms of LDL can be taken up by scavenger receptor (SR) pathways, resulting in unregulated cholesterol accumulation and foam-cell formation.

A number of SR pathways have been identified. A new class of SR, called SR class B, has been identified as the oxidized LDL receptor, with CD36 as one of its members. CD36 binds both acetylated LDL and oxidized LDL and is highly expressed on lipid-laden macrophages in the human atherosclerotic aorta. Evidence indicates that CD36 may play a key role in foam-cell formation in atherosclerotic lesions.

The new study reports that high-dose alpha-tocopherol (1200 IU/day) significantly decreased monocyte proatherogenic activity (superoxide anion release; lipid oxidation; release of cytokines such as interleukin-1-beta, tumor necrosis factor-alpha, and interleukin-6; and adhesion to endothelium) and decreased levels of soluble cell-adhesion molecules in healthy human volunteers as well as in type 2 diabetic subjects (prone to accelerated atherosclerosis).

The authors conclude that “These findings, along with other reported beneficial effects of [alpha-tocopherol] (i.e., decrease in LDL oxidation, platelet aggregation, improvement in endothelial function, decrease inmonocyte proatherogenicity, and smooth-muscle-cell proliferation) lend further support for the potential antiatherogenic effects of [alpha-tocopherol] . . . . we now report that in human monocyte-derived macrophages, alpha-tocopherol exerts novel effects of decreasing CD36 SR expression and subsequent cholesteryl ester accumulation and could thereby reduce foam-cell formation, a hallmark of the early atherosclerotic lesion.”

References

1. See www.emord.com for the latest on our continuing First Amendment battle with the FDA. Also, note that while the FDA still will not allow us to communicate on labels the health claim that vitamin E may reduce the risk of cardiovascular disease, the FDA recommends as strongly proven reducing your risk by eating low-fat and low-cholesterol diets!
2. Devaraj et al., “Alpha-tocopherol decreases CD36 expression in human monocyte-derived macrophages,” Journal of Lipid Research 42:521-527 (2001).

 

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DURK & SANDY’S ALL-NATURAL CATTLE

We own a herd of cattle, currently numbering (including calves) just over 200 head. Our cattle graze at will over thousands of acres of privately owned lush grasslands here in central Nevada. They are not vaccinated, hormone supplemented, antibiotic or otherwise medically treated, nor are they even given assistance in calving, and, except that all calves are branded and the male calves castrated (the small number of bulls doing the reproducing are carefully selected genetic breeds called Limousin and Red Angus), they live their lives until sold for beef essentially as wild animals on their own.

The cattle drink untreated natural spring water, and the grasses on which they graze are untreated (no herbicides or pesticides) and, except for the natural cattle droppings, unfertilized. During the winter, the cattle eat hay that has been harvested from these same grasslands earlier during the growing season. The cattle are not fed grain or protein supplements. Moreover, at the high altitude at which the grazing lands are located, the ultraviolet light from the sun and about 200 night/day freeze/thaw cycles per year do an excellent job of destroying parasites and bacteria living on the grasses.

We are looking for distributors of all-natural beef who might be interested in considering offering our cattle. Please contact us (concerning truckloads of our cattle only, please) c/o Life Enhancement’s

LIPOSUCTION SUCKS AWAY INSULIN RESISTANCE TOO

We have long been interested in whether liposuction, a popular form of cosmetic surgery (218,064 liposuction procedures were reported in 1998 by board-certified plastic surgeons, dermatologists, and otolaryngologists), provides health benefits by reducing the body-fat load or altering fat distribution. An article in the January 17, 2001 Journal of the American Medical Association (pp. 266-268) suggests that this is the case. Particularly in large-volume fat-removal procedures, there have been reports of reduced insulin requirements in patients with diabetes and alterations in triglyceride levels. Large-volume liposuction involves 4-5 liters of material, with rates of serious or fatal complications (such as embolism and death) in the range of 0.02% to 0.3%. (Perhaps you can stay young by staying pretty. . . .)

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MUSCLE LOSS IN ELDERLY ASSOCIATED WITH INACTIVITY AND TUMOR NECROSIS FACTOR-ALPHA

The muscle loss associated with aging leads to many problems, such as increased risk of falling and loss of strength. The mechanisms causing this muscle loss are not entirely understood. A new paper¹ reports the results of a study of the hypothesis that TNF-alpha (tumor necrosis factor alpha) expression in human muscle increases with age and contributes to the wasting of muscle. The researchers also looked at the effect of resistance exercise on the expression of TNF-alpha.

TNF-alpha has been identified as a cause of cachexia, the wasting of skeletal muscle in cancer as well as in chronic infections, rheumatoid arthritis, and other chronic diseases. Loss of skeletal muscle may also result in an increase in peripheral insulin resistance and in adiposity. TNF-alpha is a substance released by adipose tissue that is believed to be a cause of insulin resistance. It is well known that TNF-alpha and other proinflammatory cytokines (such as interleukin 6) and markers of inflammation (such as C-reactive protein) increase with advancing age. C-reactive protein is a marker for atherosclerosis. In this study, the researchers followed eight frail elderly subjects who underwent muscle biopsies before and after a resistance exercise program. Five frail elderly subjects served as nonexercising controls.

The results showed that TNF-alpha was expressed in myocytes in skeletal muscle biopsies and was expressed at higher levels than those in young subjects. After three months of resistance exercise, both TNF-alpha mRNA and protein levels decreased, in concert with increases in strength and protein synthesis.

Of course, TNF-alpha has a number of other effects besides decreasing muscle tissue (otherwise what would be the point of having it). It has antiproliferative and antiangiogenic effects. It reduces free radical generation by cancer cells (a possible early mechanism in its antiproliferative effect). A number of agents are reported to inhibit the production of TNF-alpha, including pentoxifylline, cyclosporine, N-acetyl cysteine, corticosteroids, and thalidomide.² 17-Beta-estradiol has been reported to reduce TNF-alpha-mediated LDL accumulation in the artery wall.³

References

1. Greiwe et al. Resistance exercise decreases skeletal muscle tumor necrosis factor alpha in frail elderly humans. FASEB J 15:475-482 (2001).
2. James. AIDS Treatment News 221:2 (April 21, 1995).
3. Walsh et al. 17-Beta-estradiol reduces tumor necrosis factor-alpha-mediated LDL accumulation in the artery wall. J Lipid Res 40:387-396 (1999).

 

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MUSCLE STRENGTH MAINTENANCE WITHOUT EXERCISE IN HIBERNATING ANIMALS

We have long been interested in the mechanistic basis for the maintenance of muscle during hibernation despite profound inactivity. For example, black bears stay inside their winter den for five to seven months of the year, during which their body temperature drops to 4^oC and they do not eat, drink, urinate, or defecate. They appear to engage in no physical activity, yet lose little muscular strength. It has been reported¹ that during this long period of inactivity, in which humans would lose a predicted 90% of their strength, the black bears lose less than 23% of their strength.

During the study, the bears were anesthetized and then tested on an apparatus in which a metal brace held the bear’s leg in a horizontal position, while a foot plate with a force transducer detected the evoked torque produced by the electrically stimulated tibialis anterior muscle.

The article¹ suggests that there are three mechanisms by which skeletal strength and muscle protein can be conserved: by recycling urea nitrogen back into protein synthesis, by using alternative sources of protein, or by rhythmically stimulating the muscles (shivering and undergoing isometric muscle contractions). In a commentary in another journal,² Hank Harlow, the study’s lead author, notes that the bears recycle 90% of their urea nitrogen during hibernation, while people can recycle 14% of their urea. We would love to see further investigation of this mechanism to preserve muscle mass in the absence of exercise. Harlow’s team plans to use fiber-optic probes to see if unnoticed exercise is going on in the dens, such as periodic activity “rather like a dog running in its sleep.”

References

1. Harlow et al. Muscle strength in overwintering bears. Nature 409:997(2001).
2. Bradbury. If you go down to the woods today . . . , The Lancet 357:613(2001).

 

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GOOD NEWS ON WEIGHT LOSS:
MORE ON EFFECTS OF CALCIUM ON ADIPOCYTE (FAT CELL) LIPID METABOLISM AND BODY-WEIGHT REGULATION

In the October 2000 issue of this newsletter, we discussed new findings that link higher levels of dietary calcium to reduced levels of body fat.¹ The researchers first noticed this as a possible effect when studying obese African-Americans during a clinical trial on the antihypertensive effect of calcium. In a follow-up, the same researchers used epidemiological data from the NHANES III nutritional survey of Americans and found that there was an inverse relationship (in both men and women) between calcium intake and body fat. These researchers had previously shown that agouti, an obesity gene expressed in human adipocytes, stimulates Ca²⁺ influx and promotes energy storage in human adipocytes by stimulating the expression and activity of fatty acid synthase. In transgenic mice overexpressing agouti, a Ca²⁺ channel antagonist (nifedipine) for four weeks improved insulin resistance, platelet aggregation, and blood pressure, as well as decreasing lipogenesis (synthesis of lipids) in adipocytes.

A new study² by Shi, Dirienzo, and M. Zemel has now reported the results of experimental tests of the hypothesis that suppressing 1,25-(OH)2-D (synthesized from vitamin D precursors) by increasing dietary calcium inhibits adipocyte Ca²⁺, thereby accelerating lipid catabolism and weight loss in calorie-restricted aP2-agouti mice. The same authors had recently reported that the calcitrophic hormone 1,25-(OH)2-D that has been shown to stimulate calcium influx in both vascular smooth muscle cells and pancreatic beta cells plays a role in the development of hypertension and hyperinsulinemia.

The new study examined the effect on fat and body weight of a low-calcium, calorie-restricted diet (0.4% as calcium), a high-calcium diet (1.2% of diet as calcium carbonate), and medium-dairy and high-dairy diets (1.2% or 2.4% calcium derived from nonfat dry milk, replacing 25% or 50% of protein, respectively). The bottom line was that the animals had a much greater body-weight loss on the high-calcium (calcium carbonate, 19% weight loss), medium-dairy from nonfat dry milk (25% weight loss), and high-dairy (29%)diets, as compared to only 11% body-weight loss on a calorie-restricted, low-calcium diet.

Although the basal-energy-restricted diet did not affect adipocyte lipolysis(breakdown of fats), the high-calcium diet caused a 77% stimulation of lipolysis, which was increased further by more than twofold in the medium-and high-dairy diet groups. All three high-calcium diets induced an increase in core body temperature. The authors suggest that this was caused by an increased expression of uncoupling protein 2 (UCP2), implicated in thermogenesis, in white adipose tissue, with an 80% increase reported on all three high-calcium diets.

These results are very exciting. However, as we warned in our previous discussion of the effects of calcium on body fat, do NOT take megadoses of calcium in an attempt to lose fat. In the case of calcium, RDA levels are reasonable. Excess calcium can cause kidney damage, calcium stones, and bone spurs. As has been known for some time (and was also indicated by the results in the new study), calcium from dairy products is more bioavailable than other forms of calcium.

The calcium dietary supplement we designed for our own use contains calcium plus cofactors needed to utilize or absorb calcium, including calcium ascorbate, calcium citrate, and tricalcium phosphate, plus ascorbyl palmitate (fat-soluble vitamin C), vitamin D (in the form of a precursor to the physiologically active 1,25-dihydroxy vitamin D), beta-carotene, and boron.

References

1. M. Zemel et al. Regulation of adiposity by dietary calcium. FASEB J 14:1132-1138 (2000).
2. H. Shi, D. Dirienzo, M. Zemel. Effects of dietary calcium on adipocyte lipid metabolism and body weight regulation in energy-restricted aP2-agouti transgenic mice. FASEB J 15:291-293 (2001).

 

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FAST VS. SLOW ALCOHOL METABOLISM AND THE RISK OF HEART ATTACK

The fact that, overall, moderate drinkers have a lower risk of heart attack than teetotalers has been getting around. Medical journals have agonized over the issue – gee, can we recommend moderate drinking to ourpatients when drinking is so politically incorrect? (Yes, but what is politically correct about having a heart attack?) The BATF (Bureau of Alcohol, Tobacco, and Firearms, the wonderful federal agency that brought us Ruby Ridge and Waco, among other things) is vehemently resisting the idea of allowing truthful information about the potential health benefits of moderate drinking on the labels of wine. However, the Competitive Enterprise Institute is litigating the issue on a First Amendment basis, and the BATF is likely to lose on this one.

The latest news on the magnitude of the effect of moderate drinking on the risk of heart attack may come as something of a surprise. The gene for alcohol dehydrogenase type 3 (ADH3) in humans comes in different versions (polymorphisms), which have now been shown to have a dramatic impact on the cardioprotective effects of alcohol.¹ This enzyme determines how fast ethanol is oxidized to toxic acetaldehyde in the body.

The authors examined the ADH3 genotype in 396 patients with newly diagnosed cases of heart attack among men in the Physicians Health Study. Of these, 374 were matched with two randomly selected controls each, and the remaining 22 with one control each. The ADH3 genotype was determined for all subjects. The researchers looked at the relationship between the ADH3 genotype, level of alcohol intake, and plasma HDL levels in these men and in a similar group of women.

While moderate alcohol consumption was associated with a reduced risk of heart attack in all three of the ADH3 genotype groups, the men who were homozygous for the gamma-1 allele and who consumed at least one drink per day had a relative risk of myocardial infarction of 0.62 (a risk reduction of 38%), as compared with the risk among men who consumed less than one drink per week. Men who consumed at least one drink per day and were homozygous for the gamma-2 allele had the greatest reduction in risk (relative risk, 0.14, a risk reduction of 86%); these men also had the highest HDL levels. The relationship between ADH3 genotype, level of alcohol consumption, and HDL level was confirmed in an independent study of postmenopausal women.

The ADH3 polymorphisms are thought to affect the rate of alcohol oxidation. The authors suggest that their findings are consistent with the hypothesis that a slower rate of clearance of alcohol from the bloodstream enhances the beneficial effect of moderate alcohol consumption on the risk of cardiovascular disease. Approximately half the benefit of alcohol consumption on this risk can be explained by an increase in the HDL level. This is very important because it is much more difficult to increase HDL levels than it is to reduce excessive LDL levels.

Although the authors did not expect an effect on risk of heart attack among those who did not drink alcohol, they did observe a nonsignificant risk reduction among men who didn’t drink and who were homozygous for the gamma-2 allele. It is interesting to note that about 10 grams (or approximately half a drink) of alcohol is manufactured in the body every day, so everybody is actually “drinking” a small amount of alcohol every day, whether or not they ingest it from exogenous sources.

Reference

1. Hines et al. Genetic variation in alcohol dehydrogenase and the beneficial effect of moderate alcohol consumption on myocardial infarction. New Engl J Med 344(8):549-555 (2001).

 

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NEW WEB SITE ON “ALTERNATIVE” MEDICINE

The U.S. National Institutes of Health has launched CAM on PubMed, a new subset of the National Library of Medicine’s literature-search database. This subset allows users to search peer-reviewed articles on complementary and alternative medicine. CAM already contains about 220,000 citations from 1966 on. To search CAM-related citations, click on the “limit” function in the search interface, then select “Complementary Medicine” from the “subsets” pulldown menu. www.ncbi.nlm.nih.gov/PubMed – Source: The Lancet 357:729 (2001).

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CERTAIN FRUITS CONTAIN INHIBITORS OF THE EPIDERMAL GROWTH-FACTOR RECEPTOR

A great deal of interest has developed concerning the family of epidermal growth-factor-receptor tyrosine kinases, which includes epidermal growth-factor receptor (EGFR), because many epithelial tumors (including breast cancer) express excess amounts of these proteins.¹ A new study² reports cyanidin and delphinidin, anthocyanins found in berries, grapes, and cherries, are potent inhibitors of the EGFR, shutting off downstream signaling cascades.

Anthocyanins are intensely colored compounds that contribute to the bright colors of many fruits. Depending upon individual diet, ingestion of several milligrams a day of anthocyanins would be expected. Extracts with particularly high levels of anthocyanins that are commercially available include bilberry and elderberry.

The authors tested whether the anthocyanidins cyanidin and delphinidin inhibited human EGFR extracted from cells of human vulva carcinoma. They found that these anthocyanidins potently inhibited the growth of the human large-cell lung-tumor xenograft cell line LXFL529L and, even more efficiently, the human vulva carcinoma cell line A431. Delphinidin exhibited similar levels of growth inhibition to that of (-)-epigallocatechin-3-gallate, a polyphenol that is structurally similar and found in green tea. The two anthocyanidins shut off the MAP kinase pathway activity downstream of the EGFR, a crucial signaling pathway in the regulation of cell proliferation.

The authors note that little is known about the cellular uptake, subcellular distribution, metabolism, and elimination of anthocyanins. As this study shows, however, it will be well worthwhile to learn a lot more about these colorful substances.

References

1. See, e.g., Eisenhauer. From the molecule to the clinic – inhibiting HER2 to treat breast cancer. New Engl J Med 344(11):841-842 (2001).
2. Meiers et al. The anthocyanidins cyanidin and delphinidin are potent inhibitors of the epidermal growth-factor receptor. J Agric Food Chem 49:958-962(2001).

 

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PLASMA ASCORBIC ACID CONCENTRATION INVERSELY RELATED TO ALL-CAUSE MORTALITY

Because of the large human population differences in genetic factors, diet, and lifestyle, the protective concentration and potential size of the relation between ascorbic acid, cancer, and cardiovascular disease have varied between studies. A new 4-yearprospective study of the relation between plasma ascorbic acid and mortality due to all causes, cardiovascular disease, ischemic heart disease, and cancer in 19,496 men and women aged 45-79 has been published.¹

The subjects were part of a study known as EPIC-Norfolk, a prospective population study of 30,466 men and women aged 45-79 years, resident in Norfolk, UK, who completed a baseline questionnaire survey and of whom 25,663 attended a clinic. Because the researchers requested individuals to provide detailed dietary, biological, and other health data and to be followed up over the study period, they had about a 45% response rate. The participants were therefore not a random sample. Nevertheless, they were said to be closely similar to UK population samples with respect to such characteristics as blood pressure, lipids, and anthropometry, but with a lower proportion of smokers.

The results showed that plasma ascorbic acid concentration was inversely related to mortality from all causes and from cardiovascular disease and ischemic heart disease in men and women. Risk of mortality in the top ascorbic acid quintile (20%) was about half that in the lowest quintile. Ascorbic acid was inversely related to cancer mortality in men but not in women.

The researchers determined whether individual subjects took supplements and made some corrections for it – the inverse relation between ascorbic acid and all-cause mortality was consistent and independent of other risk factors, after exclusion of smokers and then after exclusion of supplement users. However, because of the varying compositions of dietary supplements (in addition to their content of ascorbic acid), it is not possible to correct for all the influences they may have.

Nevertheless, ascorbic acid (or, as is also possible, ascorbic acid and/or other nutrients contained in the high-ascorbate foods, largely fruits and vegetables) provided significant protection. The authors calculated that in this cohort, plasma ascorbic acid was specifically related to fruit and vegetable intake and that an increase of 20 micromol/L in plasma ascorbic acid concentration was associated with an increase of about 50 g daily (or one serving of fruit or vegetable) and about a 20% decline in death due to all causes, cardiovascular disease, and ischemic heart disease.

The vitamin C supplement we designed for our own use is a more complete vitamin C supplement than most others, containing not only water-soluble vitamin C (from calcium ascorbate) but also fat-soluble vitamin C (from ascorbyl palmitate). Ascorbyl palmitate is a powerful antioxidant synergist that delivers the benefits of vitamin C to fatty tissues that normally do not get it and has also been shown to suppress cancer promotion in mouse skin.

Reference

1. Khaw et al. Relation between plasma ascorbic acid and mortality in men and women in EPIC-Norfolk prospective study: a prospective population study. The Lancet 357:657-663 (2001).

 

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ESTROGEN AND ATHEROSCLEROSIS

There is still much that is not understood about the protective effects of estrogen against the development of atherosclerosis in premenopausal women and in postmenopausal women taking estrogen replacement. Part of the difficulty in interpreting the results of various studies is that there are now two known estrogen receptors, ER-alpha and ER-beta, which have diverse effects and are found in differing ratios in different tissues.

The reasons for conducting a study of the differences between the atherosclerotic protective effects of ER-alpha and ER-beta, the authors of a new study¹ explain, is that while 17-beta-estradiol causes favorable alterations in lipoprotein metabolism, these changes appear to account for not more than 50% of the protection in humans. Moreover, several animal studies have shown full atheroprotection at 17-beta-estradiol doses that do not alter the lipid profile. These results have led to a focus on other effects of 17-beta-estradiol, such as direct effects on the vessel wall and on the processes involved in the inflammatory and fibroproliferative components of atherosclerosis, including endothelial permeability to LDL, LDL oxidation, cytokine and cell-adhesion-molecule expression, macrophage cholesterol homeostasis, vascular smooth-muscle-cell and neointimal proliferation and migration, calcification, and platelet adhesion and aggregation.

The results showed that in ovariectomized mice (female mice with their ovaries removed) that lack ER-alpha and lack ApoE (a cholesterol-carrying protein), the atheroprotection provided by 17-beta-estradiol is substantially abrogated, but it provided dramatic protection to mice who have ER-alpha but lack ApoE. This suggests that, at least in mice, 17-beta-estradiol’s protection occurred largely, but not entirely, through the ER-alpha receptor.

In the mice with ER-alpha that received the most protection, the protection seemed to take place at an early stage, as the lesions in these mice at 4 months of age rarely progressed beyond small and uncomplicated fatty streaks. The researchers suggest that a possible factor in this early protection is nitric oxide, since multiple studies have shown that estrogen increases the synthesis of nitric oxide through increased expression and activity of endothelial nitric oxide synthase.² They note that previous work by Rubanyi et al. has also shown that the basal release of nitric oxide is compromised in ER-alpha-deficient male mice.

Nevertheless, the high dose of 17-beta-estradiol used in the mice to demonstrate the reported effects also had significant adverse effects. The researchers report that “in addition to an overt enlargement of uteri, we found evidence of urinary obstruction in 24% and death in another 24% of the [had ER-alpha but lacked ApoE] mice treated with [17-beta-estradiol].” None of the mice that lacked ApoE and ER-alpha had the urinary or reproductive tract abnormalities. Moreover, the treated mice with ER-alpha but lacking ApoE also had foam-cell infiltration into subcutaneous macrophages (xanthomas, as are associated with hyperlipidemia in humans), while only two of 14 of the mice without ApoE or ER-alpha had such infiltration.

References

1. Hodgin et al., “Estrogen receptor alpha is a major mediator of 17 beta-estradiol’s atheroprotective effects on lesion size in Apoe-/- mice,” J. Clin. Invest.107(3):333-340 (2001).
2. Nitric oxide is also involved in growth hormone release.

To all our readers: we wish you a very happy and healthy new year!

“The real goal is to keep people alive forever.”

— William Haseltine, head of Human Genome Sciences in Rockville, MD, at a conference in Washington, DC on 4 Dec. 2000, marking the creation of the Society of Regenerative Medicine to promote research on “the human body’s natural ability to build, repair and maintain itself.”

[As a result of genome mapping,] “we will be able to increase the complexity of our . . . DNA without having to wait for the slow process of biological evolution. It is likely that we will be able to completely redesign [the human genome] in the next 1000 [years].”

— Physicist Stephen Hawking, addressing the eyeforpharma 2000 meeting in Basel, Switzerland in December 2000

(The above news items/quotes from Haseltine and Hawking reported in the 22 December 2000 Science.)

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HELP! WE NEED SOMEBODY!!
We need somebody who regularly visits a major university biomedical library to make copies of scientific papers for us. We will pay $6.00 per paper (or make offer) plus shipping. Please write to us care of this magazine or website.

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GOOD NEWS FOR 2001: HUMAN MAXIMUM LIFESPAN IS INCREASING

A paper in the 29 September 2000 Science¹ reports that the maximum age at death in Sweden rose from about 101 years during the 1860s to about 108 years during the 1990s. The pace of increase was 0.44 years per decade before 1969 but accelerated to 1.11 years per decade after that due to a faster pace of old-age mortality decline. The authors were able to attribute more than 70% of the rise in the maximum age at death during the period of 1861 to 1999 to reductions in death rates above age 70. (The rest is due to increased numbers of survivors to old age.) The lead author, John Wilmoth, was quoted in the October 7, 2000 The Lancet:² “Contrary to the common belief that has been stated in many scientific papers, there is no ‘fixed limit’ to the human lifespan.” “People have been saying for a long time that humans can’t live beyond 120 years, but that number was taken out of thin air. We’ve already had a well-documented case of someone who lived to age 122 [Jeanne Calment]. It wouldn’t surprise me if the world record is 125 or 150 by the year 2050.”

1. Wilmoth et al, “Increase of Maximum Life-Span in Sweden, 1861-1999,” Science289:2366-2368 (2000)
2. Larkin, “Is the Human Lifespan Limitless?” The Lancet 356:1249 (2000)

 

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FOR MEAT EATERS: HOW TO COOK A HEALTHIER HAMBURGER

By now the news has gotten around that grilling or frying hamburgers, steaks, and other meats at high temperatures results in the formation of heterocyclic amine carcinogens. However, although cooking at lower temperatures or for shorter lengths of time does result in the formation of less of these carcinogens, a different health problem may result because bacteria in the meat, such as E. coli, may not be adequately thermally inactivated. A new study¹ of the optimum temperatures for cooking hamburgers that both minimizes formation of carcinogens but destroys bacteria has reported that at 70° C (158° F) or higher, colony forming bacteria were completely inactivated. When patties were turned just once, heterocyclic amine levels increased as cooking temperatures increased. However, when patties were turned over every minute, the levels of the carcinogens were statistically lower. The internal temperature of the patties also reached 70° C sooner when they were turned over every minute, thus destroying harmful bacteria while creating far less of the heterocyclic amine carcinogens.

So, turn your hamburgers or steaks over every minute until they reach an interior temperature of 70°C (158° F) and enjoy healthier results.

1. Salmon, et al, “Minimization of Heterocylic Amines and Thermal Inactivation of Escherichia coli in Fried Ground Beef,” Journal of the National Cancer Institute92(21):1773-1778 (2000)

 

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RAISING HDL CHOLESTEROL WITH ORANGE JUICE

A new and pleasant way to increase HDL levels was reported recently.¹ Sixteen healthy men and 9 healthy women with elevated plasma total and LDL cholesterol and normal triacylglycerol (triglycerides, fats in the blood) concentrations took part in the study. Results showed that incorporation of 750 mL (3 cups), but not 250 or 500 mL, of orange juice daily increased HDL cholesterol by 21%, triacyglycerol concentrations by 30%, and folate concentrations by 18%, as well as decreasing the LDL/HDL ratio by 16%. (The orange juice was Tropicana Pure Premium orange juice.)

Although there was an increase in triacylglycerol, the increased levels did not exceed the normal range and the authors suggest that this may not be clinically significant or result in increased cardiovascular risk. The increase in HDL and reduction in LDL/HDL ratio are likely to be cardioprotective; importantly, it is easier to reduce LDL than it is to increase HDL. The authors do not recommend that consumption of large amounts of orange juice (which they estimate at approximately 20% of daily energy level) should be recommended to hypercholesterolemic individuals. Instead, they suggest that cardioprotective nutrients in amounts similar to those found in 750mL of orange juice should be ingested daily from a variety of foods. We will look forward to more studies that provide concrete information on appropriate combinations of other foods and on the active phytochemical constituents.

1. Kurowska et al, “HDL-cholesterol-raising Effect of Orange Juice in Subjects with Hypercholesterolemia,” Am. J. Clin. Nutr. 72:1095-1100(2000)

 

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TOAST YOUR GOOD HEALTH WITH CHOCOLATE
(BUT YOU STILL HAVE TO WATCH OUT FOR THE FATS, SUGAR AND CALORIES)

At the March 1999 meeting of the American Chemical Society, chemist Joe Vinson (University of Scranton, Pennsylvania) reported that a single candy bar’s worth of milk chocolate (40 grams) contains more than 300 mg. of polyphenols, equivalent to a day’s worth of fruits and vegetables. Indeed, he reported, if the candy bar is dark chocolate, it holds the equivalent of 2 days’ worth of fruits’ and vegetables’ polyphenols. This reported in the 2 April 1999 Science.

A new study¹ reports very exciting results in a chocolate feeding study in humans. Procyanidins found in chocolate are polyphenolic flavonoids. Ten healthy subjects (4 men and 6 women) ate 37 grams of a high procyanidin chocolate bar (DOVE Dark Chocolate, a commercially available confection containing 4.0 mg./g. of procyanidin) or of a low procyanidin chocolate bar (0.09 mg./g. procyanidin) after an overnight fast. Relative to the low procyanidin chocolate, the high procyanidin chocolate induced 32% increases in plasma prostacyclin and 29% decreases in plasma leukotrienes. The ratio of leukotrienes to prostacyclin, a measure of proinflammatory to antiinflammatory eicosanoid balance, decreased by 58% in cultured human aortic endothelial cells, similar to the 52% decrease in plasma of the human subjects. These results suggest protection of the vascular system, since prostacyclin prevents formation of abnormal blood clots within blood vessels, while leukotrienes stimulate them.

The reported effects were transient, however, suggesting that (as the authors note) “consumption of polyphenolics many times each day might be necessary for optimal vascular protection.” It would certainly be inadvisable to eat 37 grams of chocolate “many times” per day, but it is good to know that chocolate is yet another source of the healthful procyanidins.

1. Schramm et al, “Chocolate Procyanidins Decrease the Leukotriene-prostacyclin Ratio in Humans and Human Aortic Endothelial Cells,” Am. J. Clin. Nutr. 73:36-40 (2001)

 

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MEDIA COVERAGE OF TOBACCO INDUSTRY LIES, DAMN LIES, AND BIGOTRY TRUMP TRUTHFUL REPORTING

A little over a year ago, there was a flap over whether tobacco companies were producing nicotine-enriched tobacco, a type called Y-1. A story in The New York Timesreported that the government was investigating Brown & Williamson tobacco company executives “about efforts to genetically engineer seeds to produce plants with higher nicotine levels.”

“In January 1998, DNA Plant Technology pleaded guilty to a misdemeanor count of conspiring to illegally export the Y-1 seeds and agreed to cooperate in the Government’s continuing inquiry. Brown & Williamson officials were soon brought to testify before a grand jury in Washington. But that inquiry also died. Raymond C. Marshall, a lawyer in San Francisco who represented DNA Plant Technology, said he never heard from Justice Department officials again.”

The facts bear little relationship to the newspaper report. In fact, DNA Plant Technology Corporation did accept a contract in 1983 from Brown & Williamson, but it had nothing to do with genetically engineering high-nicotine tobacco, a very difficult project even today. Rather, the company took Y-1 seeds for tobacco containing 5% more nicotine in its leaves that had been developed in the 1970’s at a USDA agricultural research station in Oxford, NC using ordinary breeding techniques of genetic crosses and engineered it for male sterility, a necessary commercial prerequisite for legal export. All the above was reported in an unsigned editorial in the 17 November 1999 Nature Biotechnology.As the editorial noted, “Agricultural biotechology has enough public perception problems without being used as a pawn in the political crusades of mass media journalists.” However, this is par for the course concerning unpopular segments of the population, such as tobacco companies, and a continuing danger in a political system in which 51% make decisions that can be imposed upon the other 49% (or in which 51% can vote themselves perceived benefits at the expense of the 49%). Another serious problem, not discussed in the editorial, is that much of basic biomedical research and most environmental research (such as the issue of “global warming”) is funded by the federal government, which can, by funding those scientists who produce results consistent with the chosen direction of the government’s public policies (eg. its agenda), find scientific support for whatever policies they prefer while ignoring data inconsistent with those policies.

 

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IMMUNE SYSTEM DYSFUNCTION IN SYSTEMIC LUPUS CONNECTED BY BROMOCRIPTINE

Systemic lupus erythematosus (SLE) is an autoimmune disease primarily affecting young women (the female/male ratio of patients with SLE is 9:1) that can be very severe and even fatal. Studies suggest that it is associated with a hyperestrogenic state. It is known that estrogen exacerbates autoimmune diseases, which is why so many more women than men suffer from these diseases.

A new clinical study² reports on the effect of reducing prolactin, a hormone released in response to estrogen, which is an immunostimulatory molecule that may worsen autoimmune conditions. Activated B cells that are autoreactive are causative factors in SLE.

Earlier small human trials had found that the prolactin secretion blocking drug bromocriptine had had beneficial effects in patients with mild to moderate SLE. The purpose of the new study was to learn more about the mechanism of the bromocriptine effects. The results showed that in estrogen treated BALB/c mice the activation of the B cells involved in autoreactivity was mediated by prolactin. Hence, reducing prolactin levels with bromocriptine resulted in improvement in the disease.

This is a very exciting finding for autoimmune SLE and ought to be considered in other estrogen/prolactin related autoimmune conditions. Unfortunately, bromocriptine (Parlodel)^® is long past patent protection and, hence, this SLE treatment may not receive the attention it deserves.

1. Whitacre et al, “A Gender Gap in Autoimmunity,” Science 283:1277-78(1999)
2. 2. Peeva et al, “Bromocriptine Restores Tolerance in Estrogen-Treated Mice,” J. Clin. Invest. 106(11):1373-1379 (2000)

 

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A NEW OLD DRUG TO HELP SMOKERS QUIT

Methoxsalen, a drug already approved for treating psoriasis, has been found to reduce the rate of metabolic destruction of nicotine. A liver enzyme called CYP2A6, a member of the P-450 enzyme family, governs the metabolism of nicotine to cotinine in a two step process. As the enzyme removes nicotine from the bloodstream, a smoker needs to replete supplies by smoking another cigarette. It has been found that individuals with a defective CYP2A6 enzyme are protected from heavy dependency on nicotine because it is removed so slowly from their bloodstream. These people simply smoke a lot less and, because CYP2A6 converts procarcinogens found in tobacco smoke into their carcinogenic form, they are also less likely to develop smoking related cancers.

Methoxsalen turned out to be an effective inhibitor of CYP2A6. In one study, 17 smokers who had no intention of quitting were given tablets containing 30, 10, or 3.5 mg. of methoxsalen or a placebo orally, along with a 4 mg. nicotine tablet. Blood nicotine levels were measured at 30 minute intervals over 3 hours. Those who received the higher doses of methoxsalen had nicotine levels that were twice as high as those who took the 3.5 mg. dose of the drug or placebo. Those on the higher doses reported that they lost the urge to light up as often.

This may make it easier for those who make a new year’s resolution to quit smoking to actually do so. Note, however, that methoxsalen is a powerful photosensitizer, so a high SPF sunblock would be needed for any skin areas exposed to sun. Hopefully, non-photosensitizing analogs can be developed.

1. Johnston, “Psoriasis Drug Inhibits Nicotine Metabolism,” Modern Drug Discoverypp. 27-28 (Nov./Dec. 2000)

 

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LIFESPAN EXTENSION BY TELOMERASE MAY REQUIRE ONLY SHORT EXPOSURE

Since the discovery of telomeres, the chromosome ends that shorten with each cell doubling, and of telomerase, the enzyme that increases the length of telomeres, there has been considerable speculation and some experimentation concerning whether telomerase can be used to extend the lifespan of cells, tissues, or even organisms without an excessive risk of developing cancer.

A new study¹ reports that a transient exposure to human telomerase resulted in a very small average telomere elongation and yet extended the lifespan of normal human fibroblasts by 50%. The cells that were used were normal diploid foreskin fibroblasts that, at population doubling 85 (near senescent) had an insertion of DNA for telomerase. At population doubling 92, the telomerase DNA was removed, at which point the cells lost telomerase activity and showed telomere shortening over an additional 50 population doublings. The authors suggest that transient exposure to telomerase maybe a safe method for using the enzyme in producing tissue made of cells with a longer lifespan.

This may also be potentially useful for local treatment of skin cells in vivo, which are readily accessible. The $6.4 billion dollar question: Will it work as a hair restorer? It is interesting to note that mature hair follicles contain stem cells that appear to be essential for renewal of the skin.

1. Steinert et al, “Transient Expression of Human Telomerase Extends the Life Span of Normal Human Fibroblasts,” Biochem. and Biophys. Res. Commun.273:1095-1098 (2000)

 

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CHICKEN SOUP MAY MITIGATE INFLAMMATION

The much loved chicken soup used as a medicine when we have mild upper respiratory tract infections, such as “colds,” continues to yield its “secrets” to investigators. Researchers thought that chicken soup might work by having anti-inflammatory effects in the diverse conditions that it seems to help. To evaluate this, a traditional chicken soup was tested for its ability to inhibit neutrophil migration and was found to significantly do so in a dose dependent manner. (When a little chicken soup inhibited neutrophil migration, a bit more worked even better . . .) The activity was present in a non-particulate part of the soup. In fact, all the vegetables and the chicken in the soup had inhibitory activity.¹

A possibly therapeutic ingredient in chicken soup that we have reported on before is the amino acid arginine, found in relatively large amounts in chicken and turkey meat and known to be an immune system stimulant in adequate quantities. If you are a vegetarian or do not care for chicken soup, you might try taking arginine as a nutritional supplement.

1. Rennard et al, “Chicken Soup Inhibits Neutrophil Chemotaxis in Vitro,” Chest118:1150-1157 (2000)

 

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FOLIC ACID IS AN IMPORTANT REGULATOR OF GENE EXPRESSION

The important role of folic acid in preventing neural tube defects in fetuses and in reducing human bloodstream homocysteine levels thereby reducing the risk of cardiovascular disease is becoming more widely known. (No thanks to the FDA, however, which prohibited the communication of the neural tube defect information for years after other federal government agencies, such as the U.S. Centers for Disease Control and the U.S. Public Health Service, were trying to get the information to all women of childbearing age. We and our co-plaintiffs had to sue the FDA to force them to approve a folic acid/neural tube defects health claim and have had to sue them again because the FDA approved claim is grossly misleading; for example, the FDA claim does not permit the inclusion of the truthful and important information that synthetic folic acid in a supplement or a fortified food is twice as bioavailable as natural food folates. The FDA continues to prevent accurate information on the relationship between homocysteine and cardiovascular disease from being communicated in dietary supplement labels and advertising and we and co-plaintiffs have an ongoing First Amendment suit against the FDA on this issue, too. See www.emord.com.)

Much less well known, however, is the importance of folic acid in the proper regulation of genetic expression. (The FDA hasn’t even begun its molasses-like thinking process about this additional effect of folic acid.) Folic acid (as N5-methyl tetrahydrofolate) is required for the methylation of homocysteine to methionine (an important means of getting rid of cytotoxic homocysteine). The methionine is then modified to S-adenosylmethionine, a universal methyl donor in a variety of biochemical reactions, including the methylation of DNA. Hypomethylation (a deficiency of methylation) of DNA can result in the expression of genes that, with adequate amounts of methylation, would be suppressed. Hypermethylation, on the other hand, can prevent expression of genes, such as tumor suppressor genes, that should be expressed. Hence, methylation is a critical process in the control of gene expression and folic acid is an essential part of that process.

In a new study,^1,2 researchers investigated the use of a DNA methylation assay as a way to measure a functional consequence of marginal folic acid intake. As the authors noted, though the assay does indeed provide useful information concerning folic acid intake, a definition of DNA hypomethylation still needs to be established as there are no currently set normal ranges for DNA methylation. The study followed 33 healthy postmenopausal women (aged 60-85 years) on a moderately folate-depleted diet for 7 weeks, followed by 7 weeks of folate repletion with either 200 or 415 mcg. of folic acid per day (doses equivalent to 400 and 830 mcg. of natural food folates daily). Leukocyte DNA methylation was determined on the basis of the ability of DNA to incorporate methyl groups from labeled S-adenosylmethionine in an in vitro assay.

Results showed that moderate folate depletion in the subjects resulted in a significant increase in overall mean methyl incorporation into leukocyte DNA, with a total of 27 of 33 subjects showing an increase at week 7 compared with baseline. This suggests that there was a deficiency of methylation in the depleted leukocyte DNA. During repletion, a significant proportion of the subjects continued to respond with increasing methyl incorporation, which the authors interpret to mean that leukocyte DNA methylation may be slow to respond to folate repletion after depletion. They suggest that a longer repletion period or repletion with higher amounts of folic acid (larger than 415 mcg. per day) may have been required to observe significant increases in the methylation status of hypomethylated DNA in these women.

1,2. Rampersaud et al, “Genomic DNA Methylation Decreases in Response to Moderate Folate Depletion in Elderly Women,” Am. J. Clin. Nutr. 72:998-1003(2000); Jacob, “Folate, DNA Methylation, and Gene Expression: Factors of Nature and Nurture,” Am. J. Clin. Nutr. 72:903-4 (2000)

 

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AN ANALYSIS OF THE 2000 ELECTION: THE FUTURE OF FREEDOM

Wow! The election is finally over but the Second American Civil War may still be heating up! We think that the razor thin margin of victory by Bush did not reflect a lack of difference between the two Presidential candidates, as some have proposed, but a nation sharply divided between two different sets of values that boil down to the tax payers versus the tax money takers (another way to put it is the gimmees versus the wealth producers.) The basis for this war between the roughly equal (in numbers)*segments of society is that, while there is virtually unlimited potential for government to tax and redistribute income, there is little to restrain anyone from demanding more and more benefits at the expense of those who pay, obviously an unstable and morally hazardous situation. (The reason that direct taxes, such as income taxes, were not included as part of the federal government’s powers in the original Constitution and why a Sixteenth Amendment was needed to institute direct taxes was that the founders feared that direct taxes would give the federal government too much power. How right they were. Note that under our current laws, there is absolutely no entitlement by anybody to a penny of his or her own earnings, while there are numerous entitlements to other people’s money.)

Equality is often used as a moral basis for government to redistribute income. Whether people have a right to the fruits of other people’s labor simply by virtue of having been born is a question of value. However, whether equality can actually be achieved by government manipulation is an economic question that can be answered without resort to value judgements. Note that: 1) The faster technology changes, the less likely that there can be equality in the distribution of its benefits. That’s because the faster changes take place, the farther the system of constantly changing human choices is from the equilibrium (stasis) that would be required for equality to exist. An example of perfect equality is death. 2) At the same time, though, the faster technology changes, the faster that products of advanced technology become available to all, including the less well off. As an example of “trickle down” economics, a personal computer that cost $3,000 a decade ago can now be purchased for $30 at a garage sale. 3) Hence, you can have a dynamic economy with lots of opportunities and no guarantee of equal outcomes or you can have a stagnant economy within which to politically jockey for equality.

We fear that we have seen a fundamental change in the nature of American elections with the entrance of large-scale legal litigation and the open use of widespread fraud in ballot counting as a political strategy. All sorts of clever things are being hatched by lawyers. For example, think about the impact of an emerging battle in several states, including Florida, Pennsylvania, and Washington, over re-enfranchising felons, who are likely to vote overwhelmingly – perhaps 70-90% – Democratic. (In many low population rural counties where prisons are often built, the majority of residents may vote Republican, but the felons could dominate the results of local elections.) There are about 4 million convicted felons out there who are currently disenfranchised by state laws.

Criminologist Chistopher Uggen of the University of Minnesota says, “Democrats have successfully co-opted Republican policies on crime. One unanticipated cost of that strategy has been an erosion of the Democratic voter base.”

Nancy Northrup, director of the Democracy Program at New York University’s Brennan Center for Justice, is the lead attorney for the Florida ex-felons. “Disenfranchised felons used to represent 1% of Florida’s voting age population,” she says. “Now it’s 5%.” (Here is yet another social problem resulting from the “War on Drugs” which has disenfranchised many for non-violent drug offenses. Is it wise public policy to treat non-violent drug offenses as harshly as violent crimes?) Counting both inmates and ex-inmates, 24% of Florida’s voting age black males cannot vote. (See Goldhaber, “The FelonVote,” The National Law Journal, Oct. 30, 2000, pg. A1)

 

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* A 50/50 split is predicted by game theory.^1,2 Deviations from 50/50 are probably due to credibility differences between the candidates. For example, after Bush Sr. moved his lips on taxes, his base no longer supported him, and Bob Dole really was (as he was called) a tax collector for the welfare state. Clinton, despite being an exceptionally good liar and willing to use whatever means, even unconstitutional ones, to achieve his ends, remained a credible source of government goodies for his constituencies. In the 2000 election, the credibility of the two candidates appeared to be about equal to their respective constituencies; hence, the almost perfect 50/50 voter split predicted by game theory. It is easier to follow this argument if you consider, as an analogy, the relationship between populations of predator and prey. Increasing numbers of prey allow for increasing numbers of predators. If predators increase in numbers too rapidly in response to the increased prey, though, the ratio of predators to prey become too great and prey are depleted, followed by a die-back of predators.

Until recently, one of the big problems in mathematical models of predator-prey ecology is that they were inherently unstable. The models predicted that the predators would either completely consume all prey and then starve or consume nearly all of the prey and then starve. Of course, this rarely happens in nature. The flaw in the prior mathematical models was that they ignored differences in the spatial distributions of predators versus prey.The ability of prey to move away from a high predation area to an area of less predation has a profound stabilizing effect.³ That is exactly what is happening in the United States. Ten years ago we moved from Southern California, an area of high taxes and heavy land use regulations, to Central Nevada, a rural area with few regulations in a state with no income tax. If you examine the USA Today election map of counties won by Bush versus those won by Gore, you can see clearly a dramatic distinction between the urban areas where most of the tax predators live and rural areas where tax prey can still escape to. It is because of the careful design of the electoral college by the founders that the U.S. is not dominated by a few large population centers.

1. Buchanan, James, “Politics, Policy, and the Pigovian Margins” in The Collected Works of James M. Buchanan: Vol. I The Logical Foundations of Constitutional Liberty pp. 64-65, 1999, Liberty Fund, Inc., $12 pb, 8335 Allison Pointe Trail #300, Indianapolis, IN 46250-1684
2. J. Von Neumann and O. Morgenstern, Theory of Games and Economic Behavior, third ed., 1953, p. 264
3. Hastings, “The Lion and the Lamb Find Closure,” Science 290:1712-1713(2000)

If you love wealth greater than liberty, the tranquility of servitude greater than the animating contest for freedom, go home from us in peace. We seek not your counsel, nor your arms. Crouch down and lick the hand that feeds you. May your chains set lightly upon you, and may posterity forget that ye were our countrymen.
– Samuel Adams, American Revolutionary

He has erected a multitude of New Offices, and sent hither swarms of Officers to harass our people, and eat out their substance.
– The Declaration of Independence

HOMOCYSTEINE ACCELERATES CELL SENESCENCE AND SHORTENS TELOMERES

Researchers set up an endothelial-cell-culture test system to examine the effects of homocysteine on cell senescence. Their remarkable findings included the revelation that homocysteine increased the amount of telomere length lost per population doubling (a nearly threefold increase in telomere shortening), an effect that was inhibited by the peroxide scavenger catalase. Chronic exposure of the endothelial cells to homocysteine also increased the expression of two cell-surface molecules involved in vascular disease and cancer, ICAM-l (intracellular adhesion molecule-l) and PAI-1 (plasminogen activator inhibitor-1). The level of ICAM-1 and PAI-1 correlates with the degree of endothelial senescence. The authors concluded that homocysteine accelerates the rate of cellular senescence via an oxidation/reduction-dependent pathway.¹

Many of the atherogenic effects of homocysteine have been ascribed to its ability to increase hydrogen peroxide generation.¹ And, as we have reported earlier, hydrogen peroxide is also known to increase insulin resistance,² another major source of aging damage.

As the authors note, the fact that homocysteine increased the loss of telomere length with each population doubling shows that telomere length is not determined merely by the number of doublings but, as found here, can be affected by oxidation state. If so, this shows that the free radical theory of aging and the telomere theory of aging are not necessarily separate mechanisms.

Finally, previous studies done by others reported that genomic DNA isolated from areas in human blood vessels prone to atherosclerosis had shorter telomere length when compared to adjacent nondiseased areas.

Homocysteine is recognized by nearly everyone other than the FDA as an independent risk factor for atherosclerosis, though large, randomized studies determining how much homocysteine reductions of various amounts may reduce cardiovascular disease outcomes have yet to be done. Such studies probably never will be done, because vitamins cannot be patented, hence, there will be no way for the many millions of dollars invested in such expensive studies to be recovered. The level of evidence for cardiovascular protection by reducing homocysteine levels is at least as strong as that of the cardiovascular protective effects of soy and plant stanols and sterols; these are now FDA-approved claims for foods. Although supplements of folic acid and vitamins B6and B12 can lower homocysteine levels in both animals and humans, the FDA persists in violating the free speech rights of supplement producers and consumers guaranteed by the First Amendment by prohibiting a truthful health claim that folic acid and vitamins B6and B12 may reduce the risk of cardiovascular disease. We have sued to force the agency to issue the approval. See www.emord.com for the latest on the suit and on how you can help.

References

1. Xu et al., “Homocysteine Accelerates Endothelial Cell Senescence,” FEBS Letters 470:20-24 (2000).
2. Hansen et al., “Insulin Signaling Is Inhibited by Micromolar Concentration of Hydrogen Peroxide,” J. Biol. Chem. 274(35):25078-25084 (1999).

WHY PRESCRIPTION DRUGS ARE SO EXPENSIVE, AND WHAT TO DO ABOUT IT

We can think of four main reasons that prescription drugs are expensive:

1. The FDA. The agency prevents competition between prescription drugs and less expensive dietary supplements that may be able to provide similar benefits with lower risks of adverse effects and side effects – for example, finasteride vs. saw palmetto to treat benign prostatic hypertrophy. The FDA blocks competition by refusing to approve health claims for dietary supplements and fighting the free speech rights (to provide truthful health information) of dietary supplement companies to inform consumers who use supplements and want such information.

We (along with the American Preventive Medical Association, which joined us as coplaintiff and helped pay the legal bills) won a landmark court decision in Pearson vs. Shalala (U.S. Court of Appeals for the District of Columbia Circuit, 15 January 1999). The court ruled that the FDA’s prohibition of truthful, nonmisleading health claims for dietary supplements was unconstitutional and that, even if the level of scientific support for a claim did not meet an FDA-defined standard, the agency would have to approve the claim and provide a disclaimer that would prevent any potential to mislead the public. After spending some $200,000 to get that great win, the FDA has openly refused to comply with the court’s ruling, continuing to suppress the four truthful claims at issue (as well as many others). The money wasn’t wasted, however, as we continue to pursue the FDA with further legal action intended to bring the agency to heel. See www.emord.com for all the action, including briefs and oral arguments, court decisions, etc. And if the FDA’s arrogant actions infuriate you as much as they do us, please consider sending a donation to support the case. Make your check out to the Pearson & Shaw Litigation Fund and send to Emord & Associates, 5282 Lyngate Court, Burke, VA 22015. Thanks!

2. The FDA. The agency disallows the importation of FDA-approved prescription drugs manufactured by FDA-approved facilities in other countries, except by the drug manufacturers. Recent bills by Congress may order the FDA to discontinue that practice, although (as we have seen in the FDA’s abrogation of free speech rights in the case of dietary supplement health claims) they may simply refuse to obey Congress. It is up to Congress to punish the FDA for failing to obey congressional statute, such as by reducing the FDA’s budget. (If the Democrats retake the House in the upcoming election, the FDA will not have to worry about congressional oversight, since the House’s #1 FDA ally and pharmaceutical industry shakedown artist, Henry Waxman, would then be back in power.)

3. The FDA. The cost of getting approval for a single new drug entity has now reached about $500,000,000. Only large pharmaceutical companies can afford to spend that sort of money, even with a period of market monopolization through patents within which to recover their money and get a reasonable return on their investment. Approval costs are far higher here than in other advanced countries. Getting approval costs down by, for example, reducing the FDA’s authority to overseeing just safety, rather than overseeing both safety and efficacy, is one way to dramatically reduce drug costs, as well as to increase our access to many useful treatments that otherwise never reach the market due to these high costs. Let freely interacting scientists, doctors, and patients determine relative efficacy in the only way that it matters – in competition with other treatments of individual patients, whose response to a drug may vary widely.

4. The FDA. The system of patented protection of pharmaceutical drugs now includes dangerous provisions whereby the FDA can, for whatever reason it likes (though supposedly to make up for FDA delays in approval), extend (or not) the patent rights on prescription drugs by six months to three years. This has greatly expanded its power (because, for popular drugs, we are talking about billions of dollars in monopoly market rents each year) and fosters the corruption of FDA officials by creating a bribery incentive for pharmaceutical companies to try to get those extended patents and for generic drug companies to try to get the FDA not to grant them. Right now, for example, there is a battle over the right to offer generic versions of the very expensive Prozac^®(fluoxetine), the patent for which is set to expire in February 2001. The patent may be extended by the FDA for another six months, which would mean another billion or so dollars for its manufacturer. All the manufacturer had to do was to apply for a patent specifying a slightly different dose. Then it simply backs the FDA’s agenda in Congress and pays “user fees.”

The solution to these problems is, in principle, simple: get the FDA out of the drug business. The political problem of getting this done is unfortunately not so simple and is far from cheap. The $100 billion per year in prescription drug sales provides plenty of resources for paying protection money – oops, we mean, “campaign contributions” and “user fees.”

SUPPRESSION OF MELATONIN RELEASE BY DIM LIGHT

There has been growing interest in the many reported health-promoting effects of melatonin, which is released by the pineal gland in mammals during the dark (night) part of the circadian cycle. For example, tumor linoleic acid uptake and metabolism, and the growth that results from it, are suppressed by melatonin. Exposure to constant light increases the incidence of chemically induced mammary cancers, an effect that is presumed to be a result of suppression of melatonin production.

A fascinating new study shows that, at least in rats and, in earlier studies, hamsters, it takes very little light at night to suppress melatonin production and release and alter normal circadian rhythms.¹ A recent hypothesis suggests that the melatonin-suppressive effects of light at night in human populations may contribute to an increased risk of breast cancer. If humans are as sensitive as the Buffalo rats in the new study, then it doesn’t take much light to shut down melatonin production.

The male Buffalo rats were followed under three conditions: 1. Group L:D was exposed to 12 hours each of bright light (300 lux) and complete darkness. One lux is the amount of light from a regular candle at 1 meter. 2. Group L:DL was exposed to 12 hours of bright light (300 lux) followed by 12 hours of dim light (0.25 lux, which is the amount of light from a regular candle at 2 meters, or the light from the full moon). 3. Group L:L was maintained in a constant light environment at 300 lux. The animal quarters were absolutely light-tight, ensuring that no leak of light from outside would affect the results.

The rats were implanted with hepatoma 7288CTC cancer tissue and, under the experimental light conditions described, were followed and evaluated (unblinded) for a latency-to-onset of tumor growth to reach approximately the size of a pea. Tumor weights were estimated through the skin. The latency-to-onset was 10.3 ± 1.0 and 5.0 days for the L:DL and L:L groups, respectively, compared with 16.7 ± 2.3 days for the L:D group. Hence, hepatoma growth rates were two to three times greater in the L:DL and L:L groups, respectively, compared to the L:D controls.

In animals under the L:D cycle, a threefold increase in plasma melatonin levels occurred during the dark phase, whereas no nocturnal increase in plasma melatonin was evident in either the L:L or L:DL groups. In this experiment, exposure to dim light during the dark phase was as effective in suppressing the nocturnal melatonin surge as was constant light. The normal circadian rhythm of food intake was preserved in the L:DL group, however. The animals exposed to constant light consumed food throughout the 24-hour day and showed no diurnal variation in plasma lipid levels. Total food consumption was the same in all three groups, so the differences in tumor growth rate were not caused by differences in linoleic acid availability.

In conclusion, dim light at night was very effective in rats in suppressing melatonin production and release. If humans are similarly sensitive to dim light, this could have significant health consequences.

Reference

1. Dauchy et al., “Dim Light During Darkness Stimulates Tumor Progression by Enhancing Tumor Fatty Acid Uptake and Metabolism,” Cancer Letters 144:131-136 (1999).

LIPOFUSCIN ISN’T INERT GUNK – IT SPEEDS UP AGING OF CELLS IN WHICH IT IS FOUND

Lipofuscin and ceroid are fluorescent pigments of aggregated polymers derived from oxidation products of proteins and lipids, cross-linked by covalent and hydrophobic bonds. They accumulate with age in most postmitotic (nondividing) cells, such as neurons. It has been reported that lipofuscin/ceroid accumulation within aging cells is correlated with aging rate in several mammalian species, despite widely differing aging rates.¹ This correlation doesn’t tell you, though, whether the age pigments are an effect of aging, a cause, or both.

Lipofuscin and ceroid accumulation can be accelerated by increased oxygen stress and by inhibition of lysosomal proteases and lipases, which are processes that accelerate aging in general. Hence, these pigments are considered good markers of aging. What they do to cells in which they accumulate has long been unclear. A new study¹ now reports that lipofuscin/ceroid accumulation decreases proteolysis in cells, decreasing protein degradation and causing an accumulation of oxidized cell proteins.

The lipofuscin/ceroid was found to directly inhibit the activity of proteasomes, cell structures that are supposed to degrade damaged proteins. The test system was comprised of human lung fibroblast cell cultures loaded with artificial lipofuscin or ceroid pigment under conditions of normobaric hyperoxia (40% oxygen at normal atmospheric pressure). The normobaric hyperoxia caused an irreversible senescence-like growth arrest after about 4 weeks and shortened postmitotic life span from 1 1/2 years down to 3 months. By 12 weeks and thereafter, overall proteolysis was significantly depressed. Hyperoxia also caused a “remarkable” increase in lipofuscin/ceroid formation and accumulation over 12 weeks. To test whether the relation between the exposure to lipofuscin/ceroid and decreased proteolysis was causal, lipofuscin/ceroid-loaded cells were next exposed to normoxic conditions. These cells exhibited a gradual decrease in overall protein degradation over 4 weeks of treatment, whereas protein synthesis was unaffected. Proteasome-specific activity decreased by 25% over this period. Incubating purified proteasome with lipofuscin/ceroid preparation showed that the latter directly inhibited proteasomes.

This study supports the hypothesis that the accumulation of heavily damaged, oxidized, and aggregated proteins during postmitotic aging may diminish the effectiveness of proteolytic enzymes and thus accelerate aging. The study also, of course, supports the free radical theory of aging.

Reference

1. Sitte et al., “Proteasome Inhibition by Lipofuscin/Ceroid During Postmitotic Aging of Fibroblasts,” FASEB J. 14:1490-1498 (2000).

NOW WE KNOW HOW SPERM DO IT

A new report on how sperm fertilize eggs has been published.¹ The authors show that nitric oxide synthase is present at high concentrations and is active in sperm after activation of eggs by the acrosome reaction. In this reaction, there is an increase in nitrosation within eggs in seconds after insemination, and this is followed by a calcium pulse of fertilization. Microinjection of nitric oxide (NO) donors or recombinant nitric oxide synthase duplicates these events of egg activation, whereas prior injection of oxyhemoglobin, a physiological scavenger of nitric oxide, prevents egg activation.

It is interesting to note that arginine has been used to promote fertility in bulls, by increasing numbers and motility of sperm, for close to 50 years.

Reference

1. Kuo et al., “NO Is Necessary and Sufficient for Egg Activation at Fertilization,” Nature 406:633-636 (2000).

WHY THE BRITISH NATIONAL HEALTH SERVICE IS HAZARDOUS TO THE HEALTH OF THE BRITISH

An article in the September 6, 2000 Journal of the National Cancer Institute reveals even more bad news about the British National Health service and why the United States should not emulate it. All quotes below are from the article.

According to the article, the British Association of Cancer United Patients (BACUP) has just celebrated its fifteenth birthday; this organization is said (but we don’t know by whom) to have done more than any other single organization to promote patient empowerment in Britain. British patients “used to be treated like children who were ‘seen and not heard.’ They were denied clinical information as a matter of official policy; hospital notes were stamped ‘Not to be seen by the patient.’ Pharmacists were instructed not to tell patients what drugs they had been prescribed.” (D & S comment: Amazing, isn’t it, that British patients are such sheep that they have been willing to take their prescribed little white pills when they didn’t even know what was in them?)

Because of CancerBACUP and others, “old-style British paternalism is now being phased out in Britain in the name of new-style American consumerism and political correctness. New models are emerging – the ‘informed patient,’ the ‘expert patient,’ and the ‘doctor-patient partnership.'”

“The information available from treatment trials from Physician Data Query has been available for some time in the United States, whereas even now they’re not available on a wide-scale basis in the United Kingdom,” said Jean Mossman, chief executive of CancerBACUP. (D & S comment: Of course not. When the government is paying for your therapy, they sure don’t want you to know about all the options. The demand for “free” health care is always much greater than the supply.)

“UK health economists have taken up this theme in the British Medical Journal, arguing that although it may be popular and politically correct to involve the public in health care priority setting, it may not necessarily be a good thing to involve it in rationing decisions.” (!) (D & S comment: In Britain, elite committees, not the public, decide who will and who will not receive lifesaving treatment. Of course they do not want the public to be involved in rationing decisions, since very few members of the public would want to give up their own potentially lifesaving treatment, no matter how costly.)

“By taking the health care purchasing decisions away from the consumer, the [British] National Health Service improves efficiency by allowing only those people with sufficient knowledge of health care to purchase effective medicine on behalf of patients.” (D & S comment: Right, and by keeping patients out of the process, you can ensure that decisions are made impersonally and efficiently on who will live and who will die. Only the market can provide diverse medical services to a population that doesn’t want or need the same one-size-fits-all government choice of treatment.)

Offering “free” health care (whether it is “free” prescription drugs or whatever) always increases the demand for that health care. Hence, you always get rationing of the “free” stuff. Worse yet, the government doesn’t want those who are getting health care through its program to realize they are getting second-class medicine and will usually put provisions into its programs that prevent people “covered” by the program from buying the medicine they want with their own money, just as occurs in the U.S.’s Medicare today.

NEW FINDINGS ON OBESITY

Leptin Regulates Bone Mass 
New reports on metabolic correlates with adiposity (body fat) are pouring into the peer-reviewed literature. Recently it has been reported that the hormone leptin (released largely by fat cells) inhibits bone formation^1,2 and that obesity is associated with high bone mass, apparently because of leptin resistance (insensitivity to leptin) in the most common form of obesity. High bone mass may be the only important health benefit of being fat.

Regulation of Adiposity by Dietary Calcium 
The relationship of greater bone mass and obesity appears to be linked – because calcium is a major regulator of bone formation – to the findings of a new paper³ that reports evidence that dietary calcium has a regulatory effect on body fat. Increasing adipocyte (fat cell) intracellular Ca²⁺ results in a coordinated stimulation of lipogenesis and inhibition of lipolysis. The researchers first became interested in this potential relationship when they found that obese African-Americans, during the course of an unrelated clinical trial on the antihypertensive effect of calcium, lost 4.9 kg in body fat over the course of a year after their calcium intake was increased from about 400 to 1000 mg/day. Although the scientists could not understand this result at the time, they later found that increases in circulating calcitrophic hormones [1,25-(OH)2-D and/or parathyroid hormone] secondary to low-calcium diets stimulate adipocyte Ca²⁺ influx and thereby increase lipid storage.

The hypothesis was further tested by the same researchers using epidemiological data from the NHANES III nutritional survey of Americans. After controlling for energy intake, the relative risk of being in the highest quartile of body fat was set to 1.00 for the lowest quartile of calcium intake and was reduced to 0.75, 0.40, and 0.16 for the second, third, and fourth quartiles, respectively, of calcium intake for women; a similar inverse relationship was also found for men.

These researchers had previously shown that agouti, an obesity gene expressed in human adipocytes, stimulates Ca²⁺ influx and promotes energy storage in human adipocytes by stimulating the expression and activity of fatty acid synthase. Correcting elevations in intracellular Ca²⁺ in adipocytes of transgenic mice overexpressing agoutiwith a Ca²⁺ channel antagonist (nifedipine) for four weeks resulted in clinical improvements in blood pressure, insulin resistance, platelet aggregation, and left ventricular hypertrophy, as well as decreasing adipocyte lipogenesis (synthesis of lipids) and adipose tissue mass.

Moreover, the researchers noted that they found that dairy calcium exerted a greater effect on attenuating fat deposition than a comparable quantity of mineral calcium. A recent randomized clinical trial found a markedly greater weight loss (7.0 vs. 1.7 kg) in patients maintained on a milk-based diet for 16 weeks vs. those maintained on a conventional hypocaloric diet at the same level of energy intake (though, of course, the form of calcium was not the only variable, since there is much more than just calcium in milk).

In a separate study,⁴ different researchers found that, in 56 young Caucasian women 16-31 years of age, calcium intake, corrected by total energy intake, significantly predicted change in body weight and body fat. Subjects with high calcium intake, corrected by total energy intake, gained less weight and body fat. Dietary intake was assessed by 3-day diet records.

WARNING: Do not take megadoses of calcium in an attempt to lose fat. Excess calcium can cause kidney damage, calcium stones, and bone spurs. In the case of calcium, RDA levels are reasonable. It is known, however, that the calcium found in dairy products is more bioavailable than other forms of calcium.

Decreased Availability of Vitamin D in Obesity 
The increased bone mass associated with obesity is surprising in light of the findings of another new study:⁵ that vitamin D is less available in the obese, which results in both vitamin D insufficiency and secondary hyperparathyroidism.

References

1. Ducy et al., “Leptin Inhibits Bone Formation through a Hypothalamic Relay: A Central Control of Bone Mass,” Cell 100:197-207 (2000).
2. Fleet, “Leptin and Bone: Does the Brain Control Bone Biology?” Nutrition Reviews 58(7):209-211 (2000).
3. Zemel et al., “Regulation of Adiposity by Dietary Calcium,” FASEB J. 14:1132-1138 (2000).
4. Teegarden, Lin, Weaver, Lyle, McCabe, “Calcium Intake Relates to Change in Body Weight in Young Women,” FASEB J. 13(5) Abstracts, Experimental Biology 99, Washington, DC, April 17-21, 1999.
5. Wortsman et al., “Decreased Bioavailability of Vitamin D in Obesity,” Am. J. Clin. Nutr. 72:690-693 (2000).

SEROTONERGIC NERVOUS SYSTEM AND INSULIN SENSITIVITY

A new paper¹ reports a close relationship between central serotonin (5-HT) activity and insulin sensitivity in healthy young male volunteers.

The researchers set up this experiment on the basis of earlier data suggesting such a relationship, such as the findings that depressed patients have higher glucose and insulin levels in the glucose tolerance test as compared to nondepressed patients. In other studies, depressed patients have shown a decreased hypoglycemic response to insulin (decreased insulin sensitivity). Moreover, substances that increase central serotonin activity, such as the 5-HT agonist D-fenfluramine or the selective serotonin reuptake inhibitor fluoxetine (Prozac^®) have been reported to increase peripheral sensitivity to insulin and clinically improve the condition of NIDDM (non-insulin-dependent diabetes mellitus) patients.

In this study, the researchers tested the relation between central serotonergic activity and peripheral insulin sensitivity in 19 healthy male volunteers (32.33 ± 11.11 years of age) with normal levels of blood glucose and glycated hemoglobin. The mean body mass index (BMI)* of the subjects was 28.53 ± 4.39 (BMIs from 25 to 30 are considered overweight, but not obese).

The release of prolactin in response to the serotonergic activity of D-fenfluramine was used to estimate central serotonergic activity. The authors found a negative correlation between insulin sensitivity and prolactin response in these healthy volunteers, which suggests that a lower insulin sensitivity is connected with decreased central serotonergic activity.

The authors suggest that one basis for a relation between 5-HT and sensitivity to insulin could be the increase by insulin of the ratio of tryptophan to other large neutral amino acids (LNAAs) in the bloodstream, thereby increasing the relative transport of tryptophan into the brain (tryptophan and other LNAAs compete for passage across the blood-brain barrier). The insulin-related increase of plasma tryptophan relative to these other amino acids is dependent on the sensitivity of insulin receptors. Another possibility is that the relation between central 5-HT and glucose tolerance could be mediated by corticosteroids. Major depression is thought to be connected with a reduction of tone of the serotonin system and also with an increase of hypothalamic-pituitary-adrenal (HPA) activity, expressed as nonsuppression of ACTH secretion in response to exogenous dexamethasone, a corticosteroid, e.g., a failure of circulating corticosteroids to provide negative feedback to the HPA axis to prevent further release of ACTH that stimulates the release of more circulating corticosteroids. However, in this study, they did not measure corticosteroids.

The authors conclude by suggesting that “modalities which increase sensitivity to insulin can facilitate serotonin activity in the brain and thus exert some antidepressant effects.”

*BMI is body mass index, measured as the weight in kilograms divided by the square of the height in meters.

Reference

1. Horacek et al., “The Relationship Between Central Serotonergic Activity and Insulin Sensitivity in Healthy Volunteers,” Psychoneuroendocrinology 24:785-797 (1999).

It is the fundamental theory of all the more recent American law . . . that the average citizen is half-witted, and hence not to be trusted to either his own devices or his own thoughts.
– H. L. Mencken

A DIET RICH IN VEGETABLES AND FRUITS, OR DIETARY SUPPLEMENTS?

Another round of vehement disagreements has emerged in the ongoing argument over whether supplements are important for optimal health or whether one can do even better by forgetting supplements and concentrating on eating a well-balanced diet containing lots of fruits and vegetables. A recent report from the National Academy of Sciences’ Institute of Medicine recommended modest increases in intake of certain dietary constituents, such as vitamin C, but suggested that the recommended amounts can be easily obtained by most people from foods, making dietary supplements unnecessary. The July 5, 2000 Journal of the National Cancer Institute, in reporting this, says that the most consistent advice remains eating a diet high in fruits and vegetables.

Norman I. Krinsky, Ph.D., chair of the NAS Panel on Dietary Antioxidants and Related Compounds, and a professor of biochemistry at Tufts University School of Medicine, sums it up: “A direct connection between the intake of antioxidants and the prevention of chronic disease has yet to be adequately established. We do know, however, that dietary antioxidants can in some cases prevent or counteract cell damage that stems from exposure to oxidants. But much more research is needed to determine whether dietary antioxidants can actually stave off chronic disease.”

We do not think the recommendation to eat lots of fruits and vegetables rather than taking supplements is nearly as informative as those making it appear to believe. Note, for example, the following facts:

1. Fruits and vegetables each contain thousands of different chemical substances, not all of which have even been identified, let alone had their biological effects determined.

2. It is highly unlikely that every one of these thousands of different substances contributes to the health-protective effects of fruits and vegetables; in fact, some of them have toxic effects (such as solanine in tomatoes and potatoes).

3. Major protective agents in fruits and vegetables have not been identified, nor have the optimal doses of these agents been determined.

4. The protective effects of fruits and vegetables against the development of certain cancers can vary considerably, depending upon the type of cancer, smoking history, lifestyle, dietary habits, family history of cancer, gender, and demographic data.

In a recent example, the Netherlands Cohort Study of 62,573 women and 58,279 men aged 55-69 years, with 6.3 years of follow-up, found the following: 57 cases of lung cancer in never-smokers, 532 cases in current smokers, and 321 cases in former smokers. Among never-smokers, vegetable and fruit consumption were not inversely associated with lung cancer. Among former and current smokers, inverse associations with statistically significant trends were found between total vegetable consumption and lung-cancer risk. Inverse associations with cooked and raw vegetables showed statistically significant trends in current, but not in former, smokers. The inverse association with fruit consumption had a significant trend only among current but not among former smokers. Inverse association with citrus fruit was found in current smokers but not former smokers. The inverse association was stronger for some vegetables, such as cauliflower, endive, string beans, and lettuce, than for others. (It was proposed that this last effect might be due partly to their popularity among participants.) These complexities require explanations that do not currently exist. [Voorrips et al., “Vegetable and fruit consumption and lung cancer risk in the Netherlands Cohort Study on Diet and Cancer,” Cancer Causes and Control 11:101-115 (2000).]

COMPARING FRUITS AND VEGETABLES TO DIETARY SUPPLEMENTS

Comparing the health-promoting effects of diets rich in fruits and vegetables to the health effects of single antioxidant supplements (such as vitamin C or E) is worse than comparing apples to oranges, since antioxidants are known to work together in free-radical-controlling systems. Yet most randomized, double-blind, controlled studies of nutrient-disease relationships have tested only a single nutrient’s effects on the incidence of chronic diseases, e.g., the Physicians Health Study that studied the effect of beta-carotene on the risk of lung cancer. Most supplement users take supplements as combinations of nutrients, not as an individual substance. Because antioxidants work in conjunction with other antioxidants and nutrients, a combination of such supplements is likely to have a more beneficial, more physiological effect than daily supplements of just one substance.

Studies continue to be published comparing the effects of the combinations of antioxidants and other nutrients in fruits and vegetables with a single nutrient supplement. For example, in a brief communication in the 22 June 2000 Nature,Eberhardt et al. (“Antioxidant activity of fresh apples,” pp. 903-904) compared (on a per gram basis) the total antioxidant activity of apples to that of vitamin C. They found that 100 grams of fresh apples had an antioxidant activity equivalent to 1500 mg of vitamin C and that whole-apple extracts inhibit the growth of colon and liver cancer cells in vitro in a dose-dependent manner. Since they found that the actual amount of vitamin C in 100 grams of apples with skin was 5.7 mg, they point out that most of the antioxidant effect must be due to other substances in the apples. They conclude from this that “natural antioxidants from fresh fruit could be more effective than a dietary supplement.” Sure, if all you take is vitamin C, then that is likely to be true.

With more knowledge of the combined effects of antioxidants and other nutrients, it will become possible to design dietary supplements that are more effective than apples. (Remember that apples did not evolve their nutritional contents to provide health benefits for humans or other mammals, but to propagate apple seeds.) In fact, we simply do not have enough information or enough money to compare the antioxidant capacity or the cancer-retarding properties of apples to the many combinations of nutrients available as dietary supplements today. Some of these combinations may already be better antioxidants (on a per gram basis) than apples. Designing dietary supplements is at the present time as much an art as it is a science, but that is not evidence that fruits and vegetables are inherently more healthful than a properly designed dietary supplement.

It is certainly true that there is very limited information available on the effects of the combinations in multinutrient and multiantioxidant dietary supplementation, but it is also true that there is not a lot known about how the pluses and minuses of the thousands of substances in a fruit or vegetable work in human biology. The way we see it, the best advice is both to eat a diet rich in fruits and vegetables and to take dietary supplements whose health-promoting effects are supported by substantial research, even if not conclusively proven.

DO-IT-YOURSELF DRUG RESEARCH & DEVELOPMENT

A disease advocacy group, tired of waiting for drug development to treat its disease, has decided to invest in its own research and development program. Started off by a $20 million donation from the Bill and Melinda Gates Foundation, the Cystic Fibrosis Foundation announced that it will invest at least $30 million in a small biotech firm, Aurora Biosciences of San Diego, to identify compounds that might prove useful in treating CF. According to the 9 June 2000 Science, in which this is reported, the new investment represents another spinoff of the “growing trend of patient groups taking charge of biomedical research.”

If Aurora is able to identify likely candidates from the several hundred thousand molecules in its library over the next five years, the CF Foundation will pay the company an additional $16.9 million to prepare the candidates for clinical trials. Because of the immense expense of actually getting FDA approval to take a successful treatment to market, the foundation would then have to get coinvestment by a major pharmaceutical company.

THE POLITICS OF CANCER

Some facts¹ support our view that government funds research as a part of a political and self-interested agenda rather than as “pure” science unpolluted by motivations beyond understanding how things work. The federal government’s National Cancer Institute currently allocates less than 3% of its budget to primary prevention of cancer. Instead it focuses on diagnosis and treatment, essentially doing basic research that is part of drug development. (The American Cancer Society, a nonprofit charity, allocates less than 0.2% of its budget to cancer prevention.) Meanwhile, the NCI has such a close relationship to the pharmaceutical industry as to appear to be in bed with it. Dr. Samuel Broder, the former NCI director, recently admitted “that the NCI has become what amounts to a government pharmaceutical company.” Former FDA commissioners almost always end up in extremely lucrative positions at pharmaceutical companies.

Economist James Buchanan won the Nobel Prize for his innovative “public choice” theory, which shows that government agents (such as those who distribute government – actually, taxpayer – research money) act individually to further their own interests rather than promoting the interests of the public as a whole. This does not mean that every government agent is dishonest or without principles, but that each is a human being who has his or her own ideas of what should be done with the public’s money, ideas that may or may not be consistent with the public interest as a whole. The control of other people’s money by government is, no matter how good the cause may appear, a huge moral hazard.

1. As reported by Samuel S. Epstein, M.D., in the July 26, 2000 JAMA, p. 442.

THE POLITICS OF GOVERNMENT-FUNDED RESEARCH 

We have often warned people that government-funded research is not “pure” science uncorrupted by economic interests (as compared, for example, to science funded by a profit-seeking private entity). Government not only has to place a value on research in order to decide which scientific projects to fund, but to determine how policy decisions will be affected by the results of that research.

Government often funds science that supports or seems to support or can be made to appear to support its political agenda. For example, the U.S. Department of Agriculture funds much research on commercial crops, fruits and vegetables, and dietary antioxidants. However, the USDA has no political interest in promoting the dietary supplement industry; rather, it has an interest in promoting the food industry in which its regulatory efforts are invested. Moreover, the food programs of the federal government that include school lunches and food stamps require a certain level of nutrition, all of which must by law be supplied by food and not by dietary supplements. As we have noted before, scientific findings that support a higher level of recommended daily intake of nutrients would require the provision of more expensive foods (such as fruits and vegetables!) to supply them and would, therefore, add billions of dollars a year to the government’s expenses. Hence, the government continues to focus on whether evidence for increased levels of nutrients such as vitamins C and E and folic acid is “conclusive,” rather than whether the bulk of the evidence supports higher intakes. The pretense that we can (or should) do nothing until the evidence is “conclusive” is the excuse frequently used by the FDA for failing to approve health claims that provide a truthful picture of the available inconclusive evidence, a violation of the First Amendment.

HIGH BODY FATNESS, NOT LOW BODY MUSCULARITY, PREDICTS DISABILITY IN THE ELDERLY

Although one would have thought that low muscularity would be the source of most of the mobility problems of the elderly, a new study¹ reports that it is high body fatness, not low fat-free mass, that predicts such problems.

The scientists used data from the Cardiovascular Health Study to study the problem. They examined body composition and self-reported, mobility-related disability in 2714 women and 2095 men aged 65 to 100 years. The odds ratio for disability in the highest quintile of fat mass was 3.04 for women and 2.77 for men, compared with those in the lowest quintile. Low fat-free mass was not associated with a higher prevalence of disability. The increased risk of disability was not explained by age, physical activity, chronic disease, or other potential confounders.

Obesity Is a Mortality Risk Factor in the Elderly Too
Another study² reports that, contrary to an earlier study that appeared to indicate that obesity is not as risky in older as in younger individuals, obesity increased mortality in both old and young individuals. However, due to the increasing impact of age on mortality, the relative risk of obesity as a mortality risk factor is lower in older than in younger persons. For example, during the 11-year follow-up, 1.5% of reference-weight young men (30-39 at the start of the study) died, whereas 3.6% of obese men in the same age group died. In the reference-weight group of older men (60-69 at the start of the study), 25.3% died in the follow-up period, while 31.9% of the obese men in the same age group died. Hence, the relative mortality risk of obesity is higher in younger than in older men, but the mortality risk differences between obese and reference-weight groups were higher in the older than the younger men. The overall finding was that the BMI [body mass index: weight in kilograms divided by (height in meters)²] associated with the lowest mortality was 18.5-24.9 in individuals 30-74 years old.

No matter how you look at it, excess body fat is a health risk, especially if you would like to live a very long time.

1. Visser et al., “High Body Fatness, but Not Low Fat-Free Mass, Predicts Disability in Older Men and Women: The Cardiovascular Health Study,” Am. J. Clin. Nutr.68:584-90 (1998).
2. Stevens, “Impact of Age on Associations Between Weight and Mortality,” Nutrition Reviews 58(5):129-137 (2000).

SALT, OBESITY, INSULIN SENSITIVITY, AND HYPERTENSION

The recent outpouring of studies on the complex interrelationships between insulin resistance and disease has provided new insight into hypertension, cardiovascular disease, diabetes, and obesity, among others. Recent published papers bring together sensitivity to salt, salt excretion, and a possible relationship to insulin resistance.

It has been known for quite some time that high blood pressure is frequently associated with insulin resistance. Data have suggested that salt sensitivity is associated with high blood pressure in a limited fraction of the latter population. A new paper now reports that salt sensitivity is associated with insulin resistance and with a reduced fall in blood pressure during the night in essential hypertension in both diabetic and nondiabetic subjects.¹

Another paper published at about the same time reports that natriuretic peptides have a potent lipolytic effect (releasing fatty acids from fat-storage tissue) via a nonadrenergic mechanism in abdominal subcutaneous adipose tissue of healthy human subjects.²Natriuretic peptides are involved in the regulation of blood pressure, blood volume, and kidney excretion of sodium. They inhibit renin, vasopressin, and aldosterone, and markedly stimulate diuresis (elimination of water through the kidneys) and natriuresis (elimination of sodium throught the kidneys), as well as being potent vasodilators. Their potent lipolytic effect links them to insulin sensitivity, since plasma fatty acids are powerful modulators of insulin sensitivity.

For example, increasing plasma fatty acid concentration for five hours caused a reduction in insulin-stimulated muscle glycogen synthesis and whole-body glucose oxidation compared to controls in one study.³ This is presumably one reason for the reduced insulin sensitivity in obesity, where plasma fatty acid concentrations are likely to be elevated. The release of “excess” natriuretic peptides in response to salt may be a mechanistic link between those who ingest excess salt or who have salt sensitivity and the reduction of insulin sensitivity.

1. Suzuki et al., “Association of Insulin Resistance with Salt Sensitivity and Nocturnal Fall of Blood Pressure,” Hypertension 35:864-868 (2000).
2. Sengenes et al., “Natriuretic Peptides: a New Lipolytic Pathway in Human Adipocytes,” FASEB J. 14:1345-1351 (2000).
3. Shulman, “Cellular Mechanisms of Insulin Resistance,” J. Clin. Invest.106(2):171-176 (2000).

HOMOCYSTEINE ASSOCIATED WITH HOSTILITY AND ANGER

An interesting recent paper¹ reports that plasma homocysteine concentrations are positively and significantly associated with hostility in middle-aged men and women and with anger in men. This may be the mechanistic explanation, at least in part, for the known relationship between increased cardiovascular disease risk and hostility as well as the increased risk of coronary artery disease associated with both heightened expression and inhibition of anger. This suggests that folic acid, vitamin B6, and possibly vitamin B12 might be useful in the treatment of a psychological condition in some people, as well as reduce their risk of cardiovascular disease.

1. Stoney et al., “Plasma Homocysteine Concentrations Are Positively Associated With Hostility and Anger,” Life Sci. 66(23):2267-2275 (2000) (abstract only, from CA Selects: Psychobiochemistry, Issue 15, 2000).

CONJUGATED LINOLEIC ACID (CLA): DOES IT REDUCE BODY FAT IN HUMANS?

Many benefits of CLA have been reported in experimental studies involving animals such as rodents, rabbits, and pigs, including anticancer, antiatherogenic, and antidiabetogenic actions. However, little work has been done in humans. Since there have been many differences discovered in the effects of CLA in different species, including differences between mice and rats,¹ it is most welcome that two new papers^2,3on the effects of CLA in humans have now been published.

The results of these two studies overall do not appear to provide support for an effect of CLA on reducing body fat, at least in these seventeen healthy, nonobese women between the ages of 20 and 41, who were the subjects of the 64-day study. Ten of the subjects were randomly assigned to receive 3 grams per day of CLA.

The study itself was done with great care, with the subjects staying in a metabolic suite at the Western Human Nutrition Center at the University of California at Davis, where the amount and content of their diets were controlled, and even the amount of exercise was controlled. The amount of energy that each subject obtained from food was regulated so as to maintain weight during baseline. Subjects were weighed daily, and body composition was determined three times per week by total body electrical conductivity. Energy expenditure was measured once during the baseline period and twice during the intervention period.

The women fed the CLA for 64 days showed no significant change in fat-free mass, fat mass, or percentage body fat compared to the placebo group. These findings are in contrast to those of the other human CLA feeding study, the Medstat study, which reported a 20% decrease in body fat after 12 weeks of CLA supplementation (at approximately 1.8 grams per day) in free-living, healthy men and women. The authors of the new study note that there are important differences between their study and the Medstat study that might explain the discrepancy. First, in the new study, body composition was measured three times a week using a whole-body measurement, while the Medstat study measured body composition once every four weeks using infrared technology on the biceps of the better arm. Second, the Medstat study included both males and females but did not break down the results by gender. Hence, it is not clear what effects the women in the Medstat study actually experienced. Third, the new study was conducted in a metabolic suite so diet and activity could be controlled and held constant throughout the study, while the Medstat study involved free-living subjects with “no documented evidence of activity or diet intake levels.” Finally, the isomeric composition of the CLA supplement was not reported in the Medstat study and could be different from that of the new study. There are differences between the effects of these isomers (discussed in the paper). Hence, it is difficult to compare the results of the two studies.

The researchers further note that previous work with animals – such as mice, rats, and pigs – that showed a decrease in body fat was done with weanlings or adolescent animals that were not fully grown and had not established their adult body composition. They suggest that some data indicate a different effect of CLA on growing animals (by, for example, depressing body-fat accumulation via a reduction in preadipocyte number), and further work is needed to study the effects of CLA on adult animals.

The new study found no significant difference in energy expenditure or in fat oxidation during rest or walking between the treated and placebo groups. Walking did increase fat oxidation and energy expenditure in both placebo and treated subjects, as expected.

The CLA supplement used in this study included a number of isomers along with the isomer thought to be the active form, trans-10,cis-12. While previous studies showing body-fat reductions in mice used CLA supplements that contained 40-45% of the active form, the new human study’s CLA supplement contained only about 23% of this form. This is another possible explanation for the results.

Fat Didn’t Decrease, but Leptin Levels Did
Curiously, despite the lack of fat loss reported in the study, the companion study reports that there was a decrease in mean leptin levels over the first 7 weeks, followed by a return to baseline levels over the last 2 weeks. Leptin is a hormone released by fat cells that generally (though not always) correlates with the amount of fat mass. In mice fed 1% CLA by weight of their diet, plasma leptin levels were also significantly decreased after 6 weeks of treatment and then returned to base levels. The mouse study found a 50% decrease in fat after six weeks and a 43% decrease by the end of the study, even though at the end of the study there was no difference in leptin levels between the treated and control mice.

Bottom Line: Does CLA Decrease Body Fat?
It’s hard to say based upon the available human and animal research, including the new human study. More research is needed. The evidence for the anticarcinogenic effect of CLA is fairly impressive, however.

1. Moya-Camarena and Belury, “Species Differences in the Metabolism and Regulation of Gene Expression by Conjugated Linoleic Acid,” Nutrition Reviews57(11):336-340 (1999).
2. Zambell et al., “Conjugated Linoleic Acid Supplementation in Humans: Effects on Body Composition and Energy Expenditure,” Lipids 35(7):777-782 (2000).
3. Medina et al., “Conjugated Linoleic Acid Supplementation in Humans: Effects on Circulating Leptin Concentrations and Appetite,” Lipids 35(7):783-788 (2000).

VASOCONSTRICTION DURING REM SLEEP MAY INCREASE RISK OF HEART ATTACKS

REM sleep is a phase of sleep during which dreams take place and during which, surprisingly, many physiological processes resemble that of the awake state. There is much more sympathetic (adrenergic) activity during REM than non-REM sleep. A new study¹ reports that not only is there more sympathetic activation during REM sleep, but there is considerable peripheral vasoconstriction. Though the authors note that they do not have data showing that REM-related vasoconstriction also occurs in larger blood vessels, they did find that, in a canine model, experimental occlusion of the coronary arteries during REM sleep resulted in a greater-than-expected decrease in coronary blood flow.

The authors hypothesize that: “The intense sympathetic activation during REM sleep and the preponderance of REM in the early morning hours have led to the suggestion that REM sleep may be responsible for increased cardiac events seen at this time.”

1. Lavie et al., “Peripheral Vasoconstriction During REM Sleep Detected by a New Plethysmographic Method,” Nature Medicine 6(6):606 (2000)

He alone is worthy of life and freedom
who each day does battle for them anew.
– Goethe, Faust

FDA UPDATE INCLUDES GREAT NEWS!

On April 20, 1999, the U.S. District Court for the District of Columbia issued the Pearson-decision mandate to the FDA, as directed by the court of appeals; the Pearson ruling was decided by the U.S. Court of Appeals for the District of Columbia Circuit on January 15, 1999 in Pearson & Shaw et al. vs. FDA et al. The mandate compelled the FDA to implement the First Amendment disclaimer process as described by the appeals court to the FDA’s health-claims approval process. The court ruled that the FDA could not prohibit health claims outright unless they were inherently misleading (i.e., no disclaimer or additional information could render the claim nonmisleading). If a health claim is only potentially misleading (that is, some consumers may misunderstand it), the FDA must first consider the use of disclaimers to correct any potential misleadingness. The constitutionally correct remedy for truthful, but inadequate, information is to provide more information, not to prohibit the truthful information.

In early June of 1999, after seeing that the FDA was doing nothing whatsoever to implement the court’s mandate, Jonathan Emord (representing the plaintiffs) wrote a series of letters to Commissioner Henney and CFSAN Director Levitt demanding that the Pearson decision be implemented immediately and asking the FDA to provide a date by which they would agree to rule on the issue of disclaimers for the four health claims that were at issue in Pearson, the prohibition of which had been ruled unconstitutional. For months, the FDA refused to set a certain date by which they would make a decision on the health-claim approvals with disclaimers. Finally, after we filed a request for injunctive relief against the FDA in the U.S. District Court for the District of Columbia, asking that the court block the FDA from continuing to enforce the unconstitutional ban on the four Pearson claims, the FDA has now agreed to issue a decision by October 24, 2000. We await the decision on our request for injunctive relief by the district court judge, Gladys Kessler, who ruled against us before in the Pearson case we then won at the appeals court level. We will appeal if Judge Kessler denies our motion.

In the meantime, we had filed three other petitions for health claims with the FDA. The agency denied all of them, including claims that vitamin E may reduce the risk of cardiovascular disease, that folic acid, vitamin B6, and vitamin B12 may reduce the risk of cardiovascular disease, and that saw palmetto may reduce the symptoms of benign prostatic hypertrophy. In the saw palmetto case, the FDA decided that the treatment of a disease was approvable only as a drug claim [flying in the face of the meaning of “dietary supplement” and of a supplement-disease relationship as defined in the Nutrition Labeling and Education Act (NLEA, 1991) and the Dietary Supplement Health and Education Act (DSHEA, 1994)]. We have filed suit against the FDA for denial of all three claims. These cases are now on stay pending FDA’s determination by May 24, 2000 on whether to allow the two vitamin claims with disclaimers and whether to evaluate the saw palmetto claim under the drug-approval process or the health-claims review standard. Please see www.emord.com for further information or to make a donation. Many thanks to all those who have sent in donations.

GREAT NEWS FOR OUR SIDE! 
On April 27, 2000, the Grocery Manufacturers Association (GMA) filed a citizen petition with the FDA endorsing Pearson and demanding that the FDA immediately implement the constitutional mandate for free flow of information as decided in that case, both for dietary supplements and for conventional foods. The FDA has 180 days within which to respond to citizen petitions.

GMA is the world’s largest association of food, beverage, and consumer product companies, including such giants as Anheuser-Busch, Campbell Soup Company, Coca-Cola Company, General Mills, Nabisco, Nestle USA, PepsiCo, Procter & Gamble, Quaker Oats, and Unilever, with yearly American sales of $460 billion and with over 2.5 million employees in the U.S. GMA is a major political and legal threat to the FDA’s stonewalling on complying with the Pearson court decision.

We highly recommend that anyone interested in this case read the GMA’s press release, comments presented at the FDA’s recent Pearson compliance meeting, and citizen petition at their Web site, www.gmabrands.com. You will find none of the wishy-washy, compromising language that you usually find when an industrial trade group complains to a regulatory agency with which it is in bed or wishes to get in bed. The GMA attorneys clearly understand the First Amendment speech issue at stake and, in particular, recognize that the future of the food industry depends upon the communication of truthful health claims concerning foods.

In fact, as we noted in our latest article for Liberty magazine,* food companies could join the fast-growing high-tech companies in NASDAQ if truthful health claims could be made about their products. It would become profitable for food companies to invest much more money in research on the relationship between foods and disease. It would also become profitable to develop new foods (using genetic engineering), such as fruits and vegetables that make much more vitamin E and polyphenols, or cattle that make omega-3 fatty acids (like fish).¹ Or how about a potato that contains slowly digested starch (sort of a time-release source of glucose) or undigestable polymers (soluble and insoluble fiber) rather than the rapidly digested starch now found in potatoes that can cause blood-sugar spikes, hyperinsulinemia, hyperlipidemias, and more weight gain?²And let’s engineer soybeans to produce 100 times as much alpha-tocopherol and omega-3 fatty acids as omega-6 fatty acids. Would you buy delicious yet low-calorie, low-glycemic-index, high-fiber French fries that are a true health food? The way to get public support for genetic engineering is by creating versions of popular foods that provide health benefits to consumers that are greater than those provided by conventional foods – and to communicate these benefits to consumers in labels and in advertisements.

* We highly recommend this publication for freedom lovers; PO Box 1181, Port Townsend, WA 98368, 1-800-854-6991, $29.50/12 issues (1 year).

References

1. Some such work is already being done, but the future depends upon the ability of food companies to communicate to consumers the benefits of these new foods. For example, two genes for the enzyme isoflavone synthase, which catalyzes the first committed step in the biosynthesis of isoflavones, including genistein and daidzein, were isolated from soybeans and expressed in another plant that does not otherwise produce isoflavones. See Nature Biotechnology 18:208-212 (2000). Isoflavones have been shown to influence not only sex hormone metabolism and physiological activity, but also protein synthesis, malignant cell proliferation, differentiation, and angiogenesis. They are thought to be protective against some cancers. Yet many people do not like the taste of soybeans, a major dietary source of isoflavones. If consumers could get isoflavones from their favorite vegetables, it could be a tremendous benefit both for consumers, who could eat more palatable sources of healthful isoflavones, and the food companies developing and selling these new vegetables. (Don’t be surprised if there are still complaints and howls from such folks as farmers committed to raising the old-style plants, and ideologues who can’t stomach high tech or “tinkering” with Nature.)3
2. Just before we sent this issue of our newsletter to “press,” the news arrived in our copy of the May 2000 Nature Biotechnology that a scientific group has now created by genetic engineering a potato producing very high amylose (slowly digested) starch by inhibiting two enzymes that would normally make the amylopectin type of starch that is rapidly digested. See Schwall et al., “Production of Very-High-Amylose Potato Starch by Inhibition of SBE A and B,” Nature Biotechnology 18:551-554 (2000).
3. There may not be as much opposition to genetic engineering as has been suggested by public opinion polls run by environmental groups, according to a news note in the May 2000 Nature Biotechnology. A U.K. public information initiative “funded by, but not beholden to, industry” has announced poll results (from a poll conducted by professional polling organization NOP) that asked people if they “would personally eat food if they knew it was genetically modified or contained GM ingredients.” 46% of people polled said they would, as compared with 50% who said they would not. And this was in the UK, where opposition to GM foods is supposedly very high. So what is the problem now? The biggest one appears to be (surprise, surprise) the FDA, which (according to another news report in the same issue of Nature Biotechnology) is about to announce a new requirement that all foods containing GMOs must undergo premarket evaluation at the agency. Moreover, the FDA delegation representing the U.S. is not objecting to new regulations on international trade in GMOs being worked out by CODEX that are (says Henry Miller, a former U.S. FDA official and a senior fellow at the Hoover Institution, Stanford, California) “more appropriate to potentially dangerous drugs and pesticides than to gene-spliced tomatoes, potatoes, and strawberries.”

NEW SAFER CIGARETTES ONLINE

You’ve probably heard that R.J. Reynolds Tobacco Co. has developed a new type of cigarette, called Eclipse, in which the tobacco is heated, not burned. Though you still get nicotine, which has certain unhealthful effects (such as blood pressure increase), the carcinogenic effects of the smoke are reduced by 90%, which should dramatically reduce the smoker’s risk of mouth, throat, and lung cancers and also reduce the destruction of antioxidants in the smoker’s lungs and bloodstream. It would still be better not to use tobacco, but if you are going to do so, this is safer than traditional direct combustion smoking. R.J. Reynolds has decided to start off by selling the new cigarette online (www.eclipse.rjrt.com), where they can provide information on the new product, such as what is different about it and how you use it.

Another even less conventional type of cigarette, called Premier, was made available by a tobacco company several years ago, but FDA’s then Commissioner David Kessler claimed it was a nicotine delivery system and, hence, an unapproved medical device and that the FDA had regulatory authority over it. That and marketing problems knocked Premier out of the market. This time, apparently, they waited until the FDA had been determined by the US Supreme Court not to have authority over tobacco before releasing the new cigarette. (Remember that regulatory agencies such as the FDA get their legitimate authority only from the Congress and subject to Constitutional limits on government action. FDA’s authority can be changed at any time by Congress, of course, which can give FDA authority over interstate commerce in tobacco, if it wishes.)

RESISTANCE TO OXIDATIVE STRESS SPECIFICALLY, RATHER THAN STRESS IN GENERAL, MAY BE OPERATIVE FACTOR IN EXPERIMENTAL LONGEVITY

A new paper1 reports that extended longevity in Drosophila melanogaster (fruit fly) is correlated with large changes in antioxidant defense system (ADS) gene expression, accumulation of copper-zinc superoxide dismutase (CuZnSOD) protein, and an increase in ADS enzyme activities, that are not observed in 17 other (metabolic) enzymes. Thus, they suggest, longevity is associated with resistance to oxidative stress rather than being the result of some non-specific and general metabolic reorganization of the organism.

In an earlier study, the group had created several long-lived strains of Drosophila by artificial selection and reported that the only factor that robustly separated out all long-lived strains from all normal lived strains was paraquat resistance. Since paraquat increases oxidative stress, the results suggest that enhanced resistance to oxidative resistance might play a role in the Drosophila enhanced longevity phenotype. Chromosomal studies reportedly showed that it was the 3rd chromosome, and particularly the proximal portion of the left arm (3L), that was necessary for the expression of the extended longevity. The structural genes for both CuZnSOD and catalase are located on chromosome 3L.

The gene expression and protein changes were followed in a normal lifespan progenitor strain (Ra) and in an extended longevity (La) strain produced by selecting for late reproducers in the Ra strain and an La strain reverse selected (using early reproducers) for reduced lifespan, the (RevLa) strain. They then measured the levels of antioxidant and non-antioxidant gene and enzyme expression in the Ra, La, and RevLa strains, to see what changes fostered longevity. The La strain was distinguished from Ra by 1) a significantly enhanced expression of certain antioxidant defense system (ADS) mRNAs such as CuZnSOD, MnSod, and to a lesser extent catalase; 2) an enhanced level of the CuZnSOD protein; 3) a significantly increased activity of the corresponding CuZnSOD and catalase enzymes; and 4) a significantly enhanced resistance of the organism to the biological damage caused by oxidative stress. The RevLa strain differed from the La strain in having 1) a significantly decreased expression of these same ADS mRNAs; and 2) a significantly decreased activity of the corresponding ADS enzymes. The authors report that “The large and statistically significant changes in the ADS enzyme activities associated with both forward and reverse selection are specifically restricted to those ADS enzymes and are not observed in 17 other ‘ordinary’ metabolic enzymes…”

For example, selection for extended longevity resulted in a 4.2% overall increase in the general metabolic activities, whereas reverse selection for shortened longevity resulted in a 10.5% overall decline in these same values. On the other hand, CuZnSOD showed a 49.1% increase in its specific activity for the selected extended longevity, with a 25.6% decrease in the animals selected for shortened longevity.

As evidence that it is the resistance to oxidative stress rather than resistance to stress in general that is the operative factor, the authors cite their earlier study in which they developed from the Ra strain a new strain (PQR) that was extraordinarily resistant to paraquat, but rather than having higher levels of ADS, they had elevated P450 enzyme levels and depressed ADS enzyme activity levels. (Apparently these animals used the P450 enzyme system to detoxify the paraquat by converting it to another chemical species rather than increasing antioxidant defense systems to prevent oxidative damage by the paraquat.) The PQR animals had a normal longevity indistinguishable from that of Ra. Hence, the authors, conclude, it is the oxidative stress resistance that made the difference in longevity.

The results of these experiments are consistent with Dr. Denham Harman’s free radical theory of aging. If oxidative stress resistance is the key factor in longevity, an important practical question is: until we can genetically upregulate our ADS systems by a means more acceptable than caloric restriction, what is the optimum way to take exogenous antioxidants and free radical stress signaling agents to mimic that effect? The lead author of this paper, Dr. Robert Arking, was interviewed in the Journal of Anti-Aging Medicine (Vol. 3 No. 1, pp. 9-13, Spring 2000)2 and directed his remarks largely to the results of this study. He notes that in upcoming experiments, he and his colleagues will be using a microarray to look at simultaneous changes in 7,000 fly genes.

References

1. Arking et al, “Forward and Reverse Selection for Longevity in Drosophila is Characterized by Alteration of Antioxidant Gene Expression and Oxidative Damage Patterns,” Experimental Gerontology 35:167-185 (2000)
2. In commenting on why he chose Drosophila as an aging model animal, Dr. Arking notes: “Flies age, and in some ways, they age differently than humans. Very few humans, as has been written, die because they drown in mashed bananas. However, the factors that make a fly weak so that it falls into the food and drowns are not dissimilar from the factors that make a human being weak – and these include free radicals.”

UPDATE ON GLYCEMIC INDEX FOR WEIGHT CONTROL AND SLOWING AGING

In our 1986 bestseller, The Life Extension Weight Loss Program (Doubleday), we included a chapter on how eating low-glycemic-index foods might help get rid of excess body fat and help maintain normal weight, as well as help prevent the aging damage that results from processes (such as glycosylation) brought on by chronic high insulin and high glucose levels.¹ Lately, the glycemic index seems to have been rediscovered in popular weight-loss books. A pretty good guide to the glycemic index of foods, including an updated list of food measurements, is contained in The Glucose Revolution(Marlowe & Co., 1999). The authors are Jennie Brand-Miller, Ph.D., Thomas M. S. Wolever, M.D., Ph.D., Stephen Colagiuri, M.D., and Kaye Foster-Powell, M. Nutr. & Diet. We are familiar with some of Dr. Wolever’s original research in the field of glycemic-index nutrition.

The most interesting and practical piece of information we found in The Glucose Revolution is that you can slow down gastric emptying (and hence the rate of digestion) by adding acid foods to your diet. For example, the book suggests vinegar, lemon juice, acidic fruits, and sourdough bread. The book states (pg. 43) that “Within the last few years, several reports in the scientific literature have indicated that a realistic amount of vinegar or lemon juice in the form of a salad dressing consumed with a mixed meal has significant blood sugar lowering effects.” Although the book contains quite a few references, the authors have, unfortunately, provided no references for this statement. They go on to say that as little as 4 teaspoons of vinegar in a vinaigrette dressing (4 teaspoons vinegar and 2 teaspoons oil) taken with an average meal lowered blood sugar by as much as 30 percent. If so, this is a very remarkable effect.

More research on the glycemic index is appearing in the literature. For example, a 1999 study² reports that in a survey of the dietary habits of 2000 British adults between the ages of 16 and 64, the 1420 participants with complete data showed a significant negative relation between serum HDL-cholesterol concentration and the glycemic index of the diet for both men (-0.00724, 95% CL -.0101 to -0.00434, p=0.02) and women (-0.01326, 95% CL -0.0162 to -0.0102, p<0.0001). (Low glycemic index was associated with higher HDLs.) The authors found no other dietary variable, including fiber, total sugar, total starch, total carbohydrates, total fat, saturated fat, polyunsaturated fat, monounsaturated fat, or cholesterol, that was significantly related to serum HDL-cholesterol concentration.

In another recent study,³ researchers used a randomized crossover design in ten moderately overweight young men to compare the effects of a high-glycemic-index (high-GI) and a low-glycemic-index (low-GI) energy-restricted diet. The high-GI diet was 67% carbohydrate, 15% protein, and 18% fat, while the low-GI diet was 43% carbohydrate, 27% protein, and 30% fat. The amount of weight lost during the 6 days of the calorie-restricted diet was not different. However, leptin levels fell further during this period on the low-GI diet, as compared to the high-GI diet. This is interesting, since higher leptin levels in the overweight are often associated with leptin resistance. A new paper⁴ suggests that leptin is responsible for high blood pressure in the obese. The dietary study is also interesting because the leptin levels fell more in those eating a much higher-fat diet. (As you will recall, leptin is a hormone released largely by fat cells.) Still, this is a difficult study to interpret, since it is a very short-term study with only a few subjects and with very different macronutrient compositions of the two diets.

Also, see the review in the September 1999 Nutrition Reviews on glycemic index, cardiovascular disease, and aging5 and a recent article in Science News.⁶

References

1. For example, see Fukagawa et al., “Aging and High Concentrations of Glucose Potentiate Injury to Mitochondrial DNA,” Free Rad. Biol. Med. 27(11/12):1437-1443 (1999).
2. Frost et al., “Glycaemic Index as a Determinant of Serum HDL-Cholesterol Concentration,” The Lancet 353:1045-1048 (1999).
3. Agus et al., “Dietary Composition and Physiologic Adaptations to Energy Restriction,” Am. J. Clin. Nutr. 71:901-7 (2000).
4. Aizawa-Abe et al., “Pathophysiological Role of Leptin in Obesity-Related Hypertension,” J. Clin. Invest. 105(9):1243-1252 (2000).
5. Morris and Zemel, “Glycemic Index, Cardiovascular Disease, and Obesity,” Nutrition Reviews 57(9):273-276 (1999).
6. Raloff, “The New GI Tracts,” Science News 157:236-238 (2000).

NITRIC OXIDE MAY INHIBIT SMOOTH MUSCLE CELL ELASTASE ACTIVITY

Nitric oxide reduces the severity of pulmonary vascular disease in rats. So do elastase inhibitors. Elastase inhibitors are, in fact, used in humans to treat emphysema and ameliorate the disease by slowing or preventing the destruction of elastin. The authors of a new study¹ now propose that nitric oxide itself reduces elastase activity in vascular smooth muscle cells. This is very exciting because elastin destruction in arterial walls plays a major role in the loss of elasticity that takes place with aging and in hardening of the arteries.

Impaired production of nitric oxide is associated with a variety of disorders, including atherosclerosis, pulmonary hypertension, restenosis (reblockage) after angioplasty, and coronary arteriopathy after experimental heart transplantation. The changes that take place in these conditions includes smooth muscle cell proliferation, migration, and accumulation of extracellular matrix glycoproteins, such as collagen, fibronectin, and tenascin. Beneficial effects of nitric oxide in these conditions are due to its vasodilating effect plus effects on tissue remodeling (such as decreased smooth muscle cell proliferation in atherosclerotic plaques) and possibly nitric oxide’s role as an intracellular signaling molecule. Vascular remodeling that is part of the pathological processes in the above disorders includes heightened activity of proteolytic enzymes, such as elastases and matrix metalloproteinases.

The authors report that inhibition of elastase activity not only prevents the progression of vascular disease, but also appears to induce regression.

To test the effect of nitric oxide in modulating the induction of elastase in cultured smooth muscle cells, the researchers added the NO donor S-nitro-N-acetylpenicillamine (SNAP). SNAP did not suppress basal levels of elastase, but inhibited the greater-than-threefold induction of smooth muscle cell elastase elicited by serum-treated elastin (STE). Another NO donor also suppressed induction of smooth muscle cell elastase, as did a cyclic GMP mimetic. The researchers report that the suppression of STE-induced elastase activity occurred as a result of NO suppression of the signaling mechanism required for the transcription of elastase and that the effect is mediated by cyclic GMP.

The semi-essential amino acid arginine is the normal nitric oxide donor in animals, and some animal studies with arginine have shown atherosclerosis-regressing effects.

Reference

1. Mitani et al., “Nitric Oxide Reduces Vascular Smooth Muscle Cell Elastase Activity Through cGMP-Mediated Suppression of ERK Phosphorylation and AML1B Nuclear Partitioning,” FASEB J. 14:805-814 (2000).

ASKING THE WRONG QUESTIONS ABOUT FIBER SUPPLEMENTS

Two new studies published in the April 20, 2000 New England Journal of Medicine¹have delivered negative news about the ability of dietary supplements to prevent disease, in this case the ability of a high-fiber cereal supplement or a low-fat, high-fiber diet to prevent the recurrence of colorectal adenomas.

Somehow the results of these two studies are being interpreted by some media people and even some supposed dietary “experts” to bear upon the question of whether a low-fat, high-fiber diet or a high-fiber cereal supplement may reduce the risk of developing colorectal cancer. They don’t.

Colorectal adenomas are a type of tumor that can develop into a malignant cancer (up to two-thirds of all colorectal carcinomas arise from adenomas). Hence, the diet and supplement were tested in these two studies not for their ability to reduce the risk of colorectal cancer developing from normal tissue, but for their ability to reduce the risk of recurrence of an already developed tumor. These patients already had genetically damaged colon cells. While it is known, for example, that a high-fiber diet or supplement can reduce the mutagenicity of colon contents, and this mechanism might plausibly contribute to a reduction in the risk of developing colon cancer, there is no mechanism, to our knowledge, whereby a low-fat, high-fiber diet or dietary fiber supplement can reverse the genetic damage that has already occurred and has caused a colorectal lesion to develop. A fiber supplement or low-fat, high-fiber diet might reduce the risk of developing colon cancer from normal tissue and yet fail to reduce the risk of developing colon cancer from an adenoma.

It is really unfortunate that these misinterpretations of the fiber studies have been published widely in the popular press. It does a serious disservice to consumers, who may now believe that these studies prove that they cannot reduce their risk of getting colorectal cancer by eating more fiber.

Reference

1. Schatzkin et al., “Lack of Effect of a Low-Fat, High-Fiber Diet on the Recurrence of Colorectal Adenomas,” N. Engl. J. Med. 342(16):1149-1155 (2000); Alberts et al., “Lack of Effect of a High-Fiber Cereal Supplement on the Recurrence of Colorectal Adenomas,” N. Engl. J. Med. 342(16):1156-1162 (2000); Byers, “Diet, Colorectal Adenomas, and Colorectal Cancer” [editorial], N. Engl. J. Med. 342(16):1206-1207 (2000).

AN ENRICHED ENVIRONMENT STRIKES AGAIN: DELAYS ONSET OF FATAL DEGENERATIVE DISEASE IN MICE

In another remarkable demonstration of the healthful effects of an enriched environment (in this case, a cage with lots of novel and frequently changing elements to explore), mice expressing the huntingtin gene took much longer to reach the onset of their disease, a fatal neurodegenerative mouse version of Huntington’s disease, when exposed to an enriched environment as compared to the usual routine care.¹ The huntingtin gene is the same gene as the one in Huntington’s disease patients that has an expanded CAG repeat encoding an extended polyglutamine segment, which causes the disease.

Animals were tested for motor coordination every week by being placed at the end of a suspended, horizontal wooden rod. At the end of the testing at 22 weeks, only one of the environmentally enriched HD mice (14%) had failed the wooden rod test, while all those under routine care had failed.

A late component of the disease is seizures. At the end of 22 weeks, two of the nonenriched mice had them, but none of the enriched mice had them.

Reference

1. van Dellen et al., “Delaying the Onset of Huntington’s in Mice,” Nature 404:721-722 (2000).

MUSCLE STRENGTH PRESICTS LONG-TERM MORTALITY RISK IN MEN

A study of the relationship between muscle strength at midlife and long-term mortality in a group of 6040 healthy men aged 45 to 68 years at baseline has reported an association with all-cause mortality, independent of BMI (body mass index).* Maximal hand-strength tests and BMI assessments were made at baseline in 1965 to 1970, and then the group was followed for mortality for 30 years(!).

The death rates per 1000 person-years were 24.6 in those with BMI < 20, 18.5 in the middle BMI category, and 18.0 in those with BMI > 25. For grip-strength tertiles, the mortality rates were 24.8 in the lowest, 18.5 in the middle, and 14.0 in the highest third. For all BMIs, the mortality rate was lower, the greater the grip strength. The lowest relative risk (RR) of mortality over 30 years was 1.0 (reference to which all other RRs were compared) for a combination of BMI 20-24.9 and in the highest tertile for grip strength. One reason for the moderate effect of BMI on mortality in this study is that the authors removed from the analysis all subjects with documented diseases at Exam 1, as well as all deaths that happened during the first 3 years after Exam 1. For example, they removed the men with cardiovascular disease, many of whom might have been expected to have a higher BMI.

The researchers note that muscle strength depends upon both muscle and nerve function, which is why it is such a good marker for mortality.

* Body mass index is (weight in kg)/(height in meters)2.

Reference

1. Rantanen et al., “Muscle Strength and Body Mass Index as Long-Term Predictors of Mortality in Initially Healthy Men,” J. Geront: Medical Sci. 55A(3):M168-M173 (2000).

SAVING PEOPLE FROM THEMSELVES – DOES IT WORK?

Although more than 80 countries have laws that require motorists and their passengers to fasten their seat belts, there is little evidence that these laws are saving many lives, according to a report in the Jan. 29, 2000 Lancet.

The Lancet article notes that a report commissioned by the UK government’s Department of Transport and then surpressed by that agency noted that “available data for eight western European countries that introduced a seat-belt law between 1973 and 1976 suggest that it has not led to a detectable change in road deaths.” An editorial in The Lancet in 1986 reported that this failure was very disappointing in light of the 1000 lives saved per year that had been anticipated and despite 95% compliance with the law. In fact, surprisingly, in the 23 months that followed the introduction of the UK seat-belt law, the number of deaths among pedestrians, cyclists, and unbelted rear seat passengers rose by 8%, 13%, and 25%, respectively.

The authors suggest that people have an internally set amount of risk they are willing to incur and that, if risks are perceived to be lessened by, say, the enforced use of seat belts, then people increase other driving risks to again reach their preferred risk level. We agree. This is consistent with reports that have shown that legally required use of motorcycle helmets has been associated with an increased risk of motorcycle accidents.

The authors then question the effectiveness of condoms in reducing HIV infections. They cite a U.S. study finding no reduction in disease incidence in women insisting on condom use compared with non-condom users. If condom use increases (thus decreasing risk per sexual encounter) people might increase their casual sexual activity. The authors calculated that when baseline condom use is 50% and it is desired to decrease the number of unprotected sex acts, then condom use must increase to at least 67% if total sexual activity increases by 50%, and to at least 76% if total sexual activity doubles.

We would like to point out another example of this phenomenon: low nicotine, low-tar cigarettes were supposed to reduce people’s exposure to the toxic contents of tobacco smoke but this approach was thwarted by smokers taking larger puffs and holding the smoke in their lungs longer or smoking more cigarettes. The result of former FDA Commissioner David Kessler’s proposed “solution” to cigarette smoking was for FDA to take over the regulation of tobacco, to then reduce nicotine content of cigarettes over a period of a few years and finally to phase out the sales of cigarettes, would be a ludicrous failure, since people smoke as many cigarettes as needed to reach the desired intake level of nicotine. Fortunately, the U.S. Supreme Court has recognized and ruled (5-4) in late March that the FDA has no Congressionally granted authority to regulate cigarettes, though you can be sure there will be a major assault on the Congress by the Administration demanding that Congress give the FDA that authority.

Cigarettes could actually be made far safer by allowing the heating of the tobacco (rather than burning), which would deliver the desired nicotine without the accompanying carcinogenic tars, but FDA doesn’t seem interested in safer cigarettes.  In fact, several years ago, the FDA threatened a tobacco company that was test marketing such devices with felony prosecution for marketing an FDA unapproved medical device and nicotine delivery system. Their view seems to be that you should have only two choices: do it their way or die.

Thus, the attempt to induce or coerce people to accept safety measures (to protect people from themselves) may not have the benefits touted for them.  For example, since the creation of the Occupational Safety and Health Administration (OSHA), the century long decrease in workplace injuries has slowed. Do government programs enforcing the use of safety devices actually make people safer or are they just expensive feel-good programs that support large bureaucracies and attract government snoops into every aspect of our lives that contains some risk?

Richens et al, “Condoms and Seat Belts: the Parallels and the Lessons,” The Lancet 355:400-403 (2000).

WE MOVE AGAINST THE FDA AGAIN AND AGAIN AND AGAIN

We, along with our coplaintiffs, have now filed three new suits against the FDA. You can download all the briefs, which clearly explain the issues involved, from www.emord.com. The first suit challenges, as a violation of the First Amendment, of the Dietary Supplement Health and Education Act, and of the court’s mandated disclaimer approach to health claims in Pearson v. Shalala (U.S. Court of Appeals for the District of Columbia, Jan. 15, 1999), the FDA’s rejection and prohibition of two petitioned health claims (one that vitamins B6, B12, and folic acid may reduce the risk of vascular disease, and the other that vitamin E may reduce the risk of cardiovascular disease*). The second suit challenges, as a violation of the First Amendment, the Dietary Supplement Health and Education Act (DSHEA), and the court’s ruling in Pearson v. Shalala, the denial by FDA of a health claim that saw palmetto may reduce the symptoms of benign prostatic hypertrophy. (The FDA wouldn’t even consider this proposed health claim, saying that it should be considered a drug claim rather than a health claim, even though the claim and the herb met all the provisions of the DSHEA.) The third suit asks that the court hold the FDA and its responsible officers in contempt of court for their failure to permit the four health claims ruled in Pearson v. Shalala to have been denied by the FDA in violation of the First Amendment.

By this time, we shall also have filed a petition with the U.S. District Court for the District of Columbia for an injunction to prevent the FDA from enforcing its prohibition on the use of the four claims held in Pearson v. Shalala to have been denied in violation of the First Amendment. We ask the court to note that a year was held to be too long in complying with the Supreme Court’s ruling against “separate but equal” schools for blacks in Brown v. the Board of Education. The First Amendment is certainly as much of a core civil right as the 14th Amendment.

All this fun stuff can be downloaded at www.emord.com! If you would like to help us pay our share of the mounting legal bills, please send your donation (checks should be made out to Emord & Associates, with the memo section noting that they are for the Pearson & Shaw Litigation Fund) to: Emord & Associates, 5282 Lyngate Court, Burke, VA 22015. Don’t be helpless. Be part of the action by fighting back. Thank you!

* For our health claim submission, we commissioned a review of the literature on vitamin E and cardiovascular disease by William A. Pryor, Ph.D., a leading scientist studying the relationship between antioxidants and free radical disorders; he is also co-Editor-in-Chief of the highly respected Free Radicals in Biology and Medicine. Dr. Pryor has edited and done some rewriting of that review and has published it in Free Radicals in Biology and Medicine 28(1):141-164 (2000). This is an excellent review. In the abstract, Dr. Pryor notes: “There are a substantial number of trials involving vitamin E that are in progress. However, it is possible, or even likely, that each condition for which vitamin E provides benefit will have a unique dose-effect curve. Furthermore, different antioxidants appear to act synergistically, so supplementation with vitamin E might be more effective if combined with other micronutrients. It will be extremely difficult to do trials that adequately probe the dose-effect curve for vitamin E for each condition that it might affect, or to do studies of all the possible combinations of other micronutrients that might act with vitamin E to improve its effectiveness. Therefore, the scientific community must recognize that there never will be a time when the science is ‘complete.’ At some point, the weight of the scientific evidence must be judged adequate; although some may regard it as early to that judgement now, clearly we are very close. In view of the very low risk of reasonable supplementation with vitamin E, and the difficulty in obtaining more than about 30 IU/day from a balanced diet, some supplementation appears prudent now.”

LIVING LONGER AND BETTER THROUGH CHEMISTRY: DO IT YOURSELF GENE MICROARRAYS

The most promising development to date in the pursuit of longer and better human lifespans is the DNA chip or microarray. These devices consist of wafers, usually made of  glass, etched with hundreds of thousands of microscopic wells, each of which contains a short stretch of DNA or RNA. These can bond with any matching strands in a sample, the matches being identified using fluorescent tags. This allows one to identify whether and to what extent various genes are turned on or off under  particular conditions, thus quickly permitting the identification of anti-aging methods that work (compared, for example, to the gene changes induced by caloric restriction in rats, mice, fruit flies, and other organisms).

A group of California scientists has now developed a  do-it-yourself kit for building a DNA microarray¹ less expensively than those commercially available and has made the information freely available on the Web http://cmgm.stanford.edu/pbrown/mguide/. Using the website, a researcher can build a microarray for an estimated  $30,000, about half the current cost of a commercial device. You’ll also need a scanner to analyze the chips. A “freeware” database designed for microarray data has now been made available by the group to allow users to store, sort and analyze genetic data (see http://www.microarrays.org). When mass produced as consumer home health test devices, these gene arrays will probably cost only a few dollars.

Now all we have to do is make sure that government agencies like the FDA, claiming that their regulations will (among  other things) protect us from  ourselves, prevent the results  of research from being converted into actual gene therapy to put it to practical use.

Eternal vigilance is the price of liberty and of longer lifespans.

1. Dalton, “DIY Microarrayers Promise DNA Chips with Everything” Nature 403:234 (2000)

HOW THE GOVERNMENT PROTECTS THE CONFIDENTIALITY
OF YOUR MEDICAL RECORDS

When Congress passed the Health Insurance Portability and Accountability Act of 1996, it gave itself until August 1999 to enact comprehensive medical privacy legislation. If it missed the deadline, then another provision of the bill empowered the Department of Health and Human Services (DHHS) to issue such regulations. The Congress has chosen to save itself a lot of work and political hassle by irresponsibily handing the job off to DHHS.

But what DHHS has now proposed as medical records confidentialty rules is – surprise, surprise – a complete fraud. First, the proposed regulations would abolish the established principle that a patient’s consent is required before his or her medical information can be released to third parties. One provision says, “Under our proposal, most uses and disclosures of an individual’s protected health information would not require explicit authorization by the individual.” The proposed new rules allow, for example, access to patients’ medical information under the categories of “treatment, payment, and health care operations” without patients’ knowledge, consent, or even ability to track who received the information. An attorney in a litigation could obtain a patient’s medical records “with a written statement certifying that the protected health information requested concerns a litigant to the proceeding and that the health condition of such litigant is at issue in such proceedings.”

Specified medical information could be disclosed (though disclosure would not be compelled) to the police at their request to help them identify suspects, fugitives, witnesses, and missing persons, or even to determine whether a crime had occurred! (Disclosure for these purposes may not be compelled, but who is going to say “no” and run the risk of being investigated themselves? Any doctor is always at risk for being accused of prescribing too many controlled-substance painkillers.)

Moreover, incredibly, if a physician wanted to provide greater protection to his or her patients’ medical records than that provided in the DHHS regulations, it would be illegal for him or her to do so.

Agencies at almost any level of government, or private entities acting on their behalf, would have broad access to personally identifiable medical data. Release would be permitted without the patient’s consent, knowledge, or notification “for inclusion in a governmental health data system that collects health data for analysis in support of policy, planning, regulatory, or management functions authorized by law.” This includes literally hundreds of government databases.

The only disclosures that actually require patient consent are those for private activities such as sales, rental, bartering or marketing, enrollment decisions in a health plan, or use for fundraising purposes. These uses, which do require patient consent, are being touted by DHHS as a basis for their claim that these regulations “protect” medical information confidentiality. Of course, if you believe, as we do, that government is a far greater danger to privacy than these private sector entities, you know better, but watch out, they may try to tar folks who oppose these “protective” regulations as antigovernment extremists.

See Appelbaum, “Threat to the Confidentiality of Medical Records – No Place to Hide,” JAMA 283(6):795-796 (2000); for regulations, see Standards for privacy of individually identifiable health information, 64 Federal Register 59918-60065 (1999) at su_docs/aces/aces140.html.

VITAMIN C SUPPLEMENTS INCREASE PROGRESS OF ATHEROSCLEROSIS, SAYS NEW STUDY

There has been some concern about the implications of a press release sent out by the University of Southern California on March 2nd [contact: Paul Dingsdale, (323) 442-2830]. In that press release, the results are reported of a study presented at the American Heart Association’s 40th Annual Conference on Cardiovascular Disease Epidemiology and Prevention in San Diego, Calif. on March 2, 2000. The results are said to show that in people taking 500 mg a day of vitamin C (both smokers and nonsmokers), a greater progression of atherosclerosis (measured as increases in carotid artery wall thickness) occurred compared to those not taking vitamin C. Over 18 months, nonsmokers taking 500 mg a day of vitamin C had a reported 2.5-times greater increase in carotid wall thickness compared to those not taking vitamin C, while smokers taking 500 mg a day of vitamin C had a 5-fold increase in carotid wall thickness.

There are a number of problems with this study, the first of which is that it has not yet been peer-reviewed and published in a scientific journal. Hence, the raw data are not available and it is not possible to determine how the study was done, characteristics of the controls and subjects, how measurements were made, the statistical analyses, and so forth. The paper was presented as a poster at the above-mentioned conference. One generally does not send out press releases to tout the results of a study presented in a poster session at a conference and not peer-reviewed and published.

For example, the brief summation in the press release claims that the vitamin consumers in the study had the same general health characteristics and health habits as those who did not use vitamin pills. Without seeing the data, how is one to know? Moreover, it is said that about 30% of the 573 participants used vitamin supplements regularly, ranging from about 30 mg to 1000 mg of vitamin C or more a day. It is important to see how many people took how much and how they were segregated according to the dose ingested. There may have been differences in general health characteristics and health habits between those taking the larger doses of vitamin C compared to the smaller doses, even if the characteristics and health habits were similar for vitamin C users as a whole compared to non-vitamin users. For example, people with greater risk because of having higher cholesterol levels may have been more likely to take larger amounts of vitamin C. Without this information, it is not possible to assess the reported results for the study.

As Dr. Jeffrey Blumberg, Chief of the Antioxidants Research Laboratory at the U.S. Department of Agriculture’s Human Nutrition Research Center on Aging at Tufts University commented, “This is a preliminary epidemiological study, and it is important to put the reported findings in the context of all the available information. This is the first report of any negative effect of vitamin C on the arteries, in contrast to the totality of data about vitamin C and health. A number of other studies suggest a positive effect of vitamin C on arterial health, and the USC researchers offered no plausible mechanism by which vitamin C could have the adverse effect observed in this study.” Dr. Balz Frei, professor and director of the Linus Pauling Institute, noted that “The results from the study presented last week, in fact, are in direct conflict with a study published in 1995 in the American Heart Association journal Circulation. That research found a significant reduction in carotid artery wall thickness in people over 55 who consumed about 1000 mg or more of vitamin C a day, compared to those consuming less than 88 mg a day.” Frei said the new vitamin C report did not put its findings in the proper context of hundreds of existing studies demonstrating the health benefits of vitamin C.

Meanwhile, the USC press release states that the study’s lead author, James H. Dwyer, Ph.D., “suggests that anyone interested in vascular health and vitamins should look to the American Heart Association to learn about the respected group’s dietary recommendations.” The American Heart Association is one of the groups that filed an amicus curiae brief on the (losing) side supporting the FDA in Pearson v. Shalala; in other words, the AHA supported FDA’s unconstitutional restrictions on the communication of truthful information (with disclaimers if necessary to prevent consumer misunderstanding) concerning the relationship between dietary supplements and cardiovascular disease. While this is not a scientific argument against the credibility of the vitamin C study, it is a good reason to look long and hard at the claimed results. When you mix politics with science, you rarely get good science.

Council for Responsible Nutrition press release; contact Cyndie S. Sirekis, (202) 263-1002.

PERSISTENCE OF MEMORY

A new study has vindicated the views on memory of William James. As James said on p. 659 of his 1890 book, The Principles of Psychology, “Memory being . . . altogether conditioned on [the ability to excite] brain-paths, its excellence in a given individual will depend partly on the number and partly on the persistence of these paths.” He maintained that memory could be improved by establishing a large network of memories with many cross-connections that would make it easier to make associations with and access a new memory.

The new study examined the effect on memory of knocking out NMDA receptors only within the CA1 region of the hippocampus in mice. It is well known that the hippocampus is important as part of the memory system, especially in mediating connections with diverse and interconnected regions of the cerebral cortex. However, the hippocampus is only a part of this process since, for example, it is not necessary for the recall of long-term memories.

A previous study had found that CA1-NMDA knockout mice had severely impaired spatial learning and memory. The new study found that their mice with the same defect were severely impaired across a broad range of nonspatial learning tests. The researchers tested James’ hypothesis by exposing the impaired mice to an enriched environment (lots of toys and other things to explore) that would presumably help establish many memory interconnections. Examination by electron microscopy showed that the number of synaptic connections in the brain was increased under conditions of enrichment in normal mice, but also in the mutant mice without CA1-NMDA receptors. Incredibly, the enrichment almost eliminated the memory defects observed in the NMDA knockout mice, as well as (as expected) increasing learning performance in normal mice. One possible explanation is that increased connectivity in the neocortex, which retained its normal NMDA receptors, could compensate for a hippocampus lacking its NMDA receptors.

These findings are consistent with reports on the improved maintenance of learning and memory in aging individuals with self-selected enriched environments; for example, highly educated people seem to be less likely to suffer from Alzheimer’s dementia, perhaps by maintaining synaptic connections, by having more to begin with, having larger numbers of memory interconnections, and running out the clock.

The effectiveness of an enriched environment in improving learning and memory continues to impress. And at the same time, it helps to vindicate the prescient author of a 110-year-old hypothesis concerning how memory works.

Eichenbaum and Harris, “Toying with Memory in the Hippocampus,” Nature Neuroscience 3(3):205-206 (2000); Rampon et al., Nature Neurosci 3:238-244 (2000).

RETURN TO LEPTIN AS A TREATMENT FOR OBESITY

We have written in earlier newsletters on the potential of the hormone leptin as a treatment for obesity. Leptin is released largely by fat cells (adipocytes), but recent research indicates that it can be released by muscle cells as well. When leptin levels are low, it is a signal of inadequate fat stores (food intake is low), and it increases the release of neuropeptide Y, among other things, to increase eating, as well as promoting a number of metabolic changes to conserve energy. Decreased leptin levels may be a part of the mechanism for changes induced by caloric restriction. Higher leptin levels signal plenty of stored body fat, and they decrease food intake and increase energy output, as well as increasing fat use for energy.

Though leptin levels are generally higher in obese people because of much greater fat mass, these higher leptin levels are often ineffective in obese individuals in reducing appetite, increasing metabolic rate, increasing the use of fat for energy, and increasing physical activity. This is called leptin resistance (analogous to the insulin resistance associated with high insulin levels in the obese), perhaps caused by the downregulation of leptin receptors.

Leptin injections have recently been tried as a treatment for obesity. Although for most experimental subjects, leptin did induce some weight loss, it was not too impressive. A letter in a recent Journal of the American Medical Association suggests some reasons why this may be so.

The authors state that leptin is characterized by what is called nyctohemeral rhythms, with serum leptin concentrations being highest around midnight. They note that this resembles the circadian rhythmicity of many other hormones, such as thyrotropin and prolactin. The leptin peak concentration precedes the peak concentrations of cortisol and growth hormone. In other words, just as there are physiological variations in growth hormone, with peaks appearing at specific times (such as 90 minutes after falling asleep), leptin concentrations vary such that giving exogenous leptin at one time may not produce the same results as giving it at another time.

Furthermore, the authors say, total circulating leptin levels exhibit a pattern indicative of pulsatile release, as is the case for other hormones, such as insulin. The pulse pattern for leptin shows a duration of approximately 30 minutes and is inversely related to rapid fluctuations in plasma cortisol and adrenocorticotropic hormone levels. (This is consistent with an earlier report that glucocorticoids are counterregulatory to leptin.) The authors believe that the pulsatile release of leptin is crucial for the attainment of its biological effects and may help explain the not too impressive effects of leptin treatments for obesity in recent clinical trials. (This is also consistent with reports for insulin in which pulsatile administration of a certain amount of insulin results in a larger biological effect than administration of the same amount of insulin in a nonpulsatile fashion.)

As with growth hormone administration, the physiological features of endogenous hormone release provide a pattern for administering exogenous hormone in order to get optimal biological effects without undesirable side effects. Perhaps leptin treatment may turn out to be more useful than studies have so far found.

Fruhbeck et al., “Chronobiology of Recombinant Leptin Therapy,” JAMA 283(12):1567 (2000); also, see Licinio et al., “Human Leptin Levels are Pulsatile and Inversely Related to Pituitary-Adrenal Function,” Nature Medicine 3:575-579 (1997); Gura, “Leptin Not Impressive in Clinical Trial,” Science 286:881-882 (1999); Zakrzewska et al., “Glucocorticoids as Counterregulatory Hormones of Leptin: Toward an Understanding of Leptin Resistance,” Diabetes 46:717-719 (1997).

This newsletter is written by scientists Durk Pearson & Sandy Shaw^® for other scientists studying aging and for interested physicians and laypersons, as well as for lawyers interested in promoting medical freedom of choice and Constitutional government. The information provided here is not intended as a replacement for professional medical or legal advice.

FDA UPDATE: FDA’S TEN-YEAR PLAN 

The FDA’s newly announced Ten-Year Plan for Dietary Supplement Strategy is a real laugh. (Those who want to read the whole thing can download it at http://vm.cfsan.fda.gov/~dms/) The FDA states, as the goal of its Ten-Year Plan, that, by the year 2010, it will have established a “science-based regulatory program that fully implements the Dietary Supplement Health and Education Act of 1994.” So  it only takes them (if they meet their “goal”) sixteen years to implement the DSHEA.

Many of the items listed in the Ten-Year Plan as subgoals, such as defining the difference between a dietary supplement and a drug and defining when a disease claim for a dietary supplement becomes a drug claim, are issues that have already been decided in the relevant congressional statute (DSHEA) that determines the extent of FDA authority over dietary supplements. The classes of substances that qualify as dietary supplements are explicitly given in the DSHEA, which also makes it clear that a truthful statement of a substance-disease relationship about a dietary supplement is not to be regulated as a drug claim.

FDA also proposes to “clarify” the regulation of a “dual status” product, which is a substance that is used both as a drug and as a dietary supplement. An example is beta-carotene, which is used as a drug (at high dose levels) in the treatment of xeroderma pigmentosum and which is, of course, also a dietary supplement.  However, there is nothing for the FDA to “clarify,” since beta-carotene qualifies as a dietary supplement under the DSHEA. Presumably, what the FDA hopes to do is to prohibit sellers of dietary-supplement beta-carotene from letting consumers know how beta-carotene is also used as a drug. If a company could simply sell beta-carotene while providing truthful information about its use at high dose levels for treating xeroderma pigmentosum, who would be interested in getting FDA approval to sell beta-carotene as a drug? Yes, this is a problem for the FDA, but we do not see how the communication of such information can be prohibited without being in violation of the First Amendment.

FDA FINALIZES ITS RULES ON STRUCTURE-FUNCTION CLAIMS FOR DIETARY SUPPLEMENTS 

The FDA has decided what it will allow as “structure-function” claims, non-disease claims that, under a provision of the DSHEA, may be provided on labels and in advertisements for dietary supplements without getting FDA’s preapproval. “Health claims,” which convey information on supplement-disease relationships, require FDA preapproval. However, under the court ruling in Pearson v. Shalala (see www.emord.com for the entire text of the ruling), the FDA may prohibit only health claims that are “inherently misleading” (i.e., false) and must approve the remaining claims, with reasonable disclaimers if FDA considers them necessary to avoid consumer misinterpretation.

FDA has now “clarified” the “structure-function” claims that are allowed without its approval under the DSHEA. (Another way to look at it is that “structure-function” claims are preapproved by Congress, hence you don’t need to get FDA approval, since the Congress’s authority is above that of an executive agency.)

The FDA, in fifty pages of detailed instructions and examples, has confused the issue totally. For example, the FDA says you can point out that a supplement “helps maintain a healthy cholesterol level,” but you  can’t say that a supplement helps prevent an unhealthy cholesterol level, such as by reducing it. The FDA says that the latter statement would suggest prevention of a disease, while the former wouldn’t. Right. One severe problem with this is that one may wonder what the meaning of “helps maintain a healthy cholesterol level” can possibly be if it can’t mean that the supplement may reduce cholesterol levels or, to put it another way, may prevent a rise in cholesterol levels. The reason for this strange interpretation by FDA is that, even if diseases are not mentioned explicitly in a structure-function claim, a consumer might recognize the implication of a structure-function in relation to a disease. For example, one might recognize a claim that an antioxidant supplement reduces the risk of LDL oxidation as a claim about the possible reduction of the risk of atherosclerosis. Hence, FDA is trying to eliminate all structure-function claims where somebody might infer an effect of the supplement on a disease. This is, of course, the category into which nearly all the interesting structure-function claims are likely to fall and thus be converted by FDA to “health claims,” which require FDA preapproval.

The structure-function rules are a tissue of First Amendment violations. An interesting part of the rule is the FDA’s analysis of how and whether the First Amendment applies to their structure-function rules.  (We were told by Jonathan Emord that a lawyer working at the FDA told him that until the court decision in Pearson v. Shalala, the FDA did not even know that the First Amendment applied to them!!)

The FDA cites early court decisions in commercial speech jurisprudence, such as Central Hudson and the Virginia State Board of Pharmacy, rather than the newer court decisions that have displaced them, such as 44Liquormart, Coors, and Pearson v. Shalala, in which commercial speech is given strong First Amendment support. For example, in the decision in Central Hudson, the U.S. Supreme Court held that “commercial speech is such a sturdy brand of expression that traditional prior restraint doctrine may not apply to it,” a view that is not favored in the courts any longer.

The FDA states that prior restraints on truthful speech are allowed for substances for which the FDA has not approved safety and efficacy. The DSHEA grants FDA no such authority, nor could it in the first place, because the First Amendment trumps congressional statute. In fact, the DSHEA stated that neither dietary supplements nor dietary supplement health claims may be regulated as if they were drugs.  Dietary supplements are not required to pass FDA tests for safety and efficacy. The FDA does have safety authority, but the burden of proof is on them if they wish to remove something from the market as unsafe.  The court ruling in Pearson v. Shalala made it clear that where speech is truthful, FDA may not prohibit it outright, but may require disclaimers to clarify potentially misleading statements.

Possibly the biggest laugh in the whole of FDA’s First Amendment analysis is their claim that: “As a government agency with no financial stake in either permitting or denying claims, FDA is in a position to evaluate the strength of the safety and efficacy evidence objectively.” The facts strongly suggest otherwise. The FDA receives close to a billion dollars a year from pharmaceutical companies as “users’ fees.” If the FDA cannot protect the market for FDA-approved drugs going through the long and expensive FDA process, then pharmaceutical companies may decide their “users’ fees” are a waste of their money. Hence, the FDA has a huge financial stake in “either permitting or denying” health claims for dietary supplements in competition with pharmaceutical drugs.

Finally, and most astonishingly, the FDA boldly rejects the court’s decision in Pearson v. Shalala, declaring itself to be above the legislative and judiciary branches of the federal government and, indeed, above the Constitution itself! The FDA says that having to [as the court ruled] permit all health claims but those that are inherently misleading (i.e., false), though the FDA can require disclaimers when reasonably necessary to prevent potentially misleading connotations of health claims, would be “untenable,” since companies could avoid the time and expenses of complying with new drug regulations by merely attaching a disclaimer to a disease treatment or prevention claim, and – you better grab your hanky – “the long-standing system of drug regulation in this country would be eviscerated.” A few comments on this performance: First, one of the clearly stated purposes of the DSHEA was to allow manufacturers and marketers of dietary supplements to avoid “the time and expenses of complying with new drug regulations” in the communication of truthful information about supplements. Second, the First Amendment trumps any “long-standing system of drug regulation.” Finally, the FDA cries wolf, since most pharmaceutical drugs would not qualify as dietary supplements, hence those unfortunates manufacturing and marketing them will still have to comply with FDA’s drug regulations. Perhaps they are concerned about investment money flowing into dietary supplements rather than prescription drugs. . . .

The FDA pulls out the worn, old argument that the average consumer “does not possess the medical and scientific expertise necessary to evaluate claims about the effect of a product on disease.” The First Amendment does not permit the government to prohibit the communication of complex, hard-to-understand, but truthful, information. Let the FDA provide counterinformation.

MORE SUITS TO COME – YOU CAN HELP 

We close this section by noting that a group of us are continuing to attack the FDA in the courts (see the following for more). If you would like to help the two of us pay our share of the mounting legal bills, please send a donation for the Pearson & Shaw Litigation Fund to Emord & Associates, 5282 Lyngate Ct., Burke, VA 22015. We appreciate your help and encouragement.

NEW LAWSUIT UPS THE ANTE AS FDA CONTINUES TO STONEWALL 

One year after the January 15, 1999 landmark decision in Pearson v. Shalala in which the Court of Appeals for the District of Columbia Circuit ruled 3-0 (appeal for rehearing en banc turned down 11-0; not appealed to the U.S. Supreme Court) that the FDA’s health-claims approval process violated the First Amendment of the United States Constitution, the FDA has not complied with the court’s order. The court ruled that the FDA had to approve all health claims that were not “inherently misleading” (i.e., false), but could require disclaimers if the agency thought that was reasonably necessary to prevent potentially misleading conclusions by consumers.

In the year since then, the FDA has not approved any of the four health claims that were the subject of Pearson v. Shalala and has rejected two additional proposed health claims filed by a group of us: one that folic acid, vitamin B6, and vitamin B12 may reduce the risk of cardiovascular disease, and the other that vitamin E may reduce the risk of cardiovascular disease.  FDA has refused to implement the Pearson court decision’s disclaimer approach to potentially misleading health claims, but continues to prohibit them outright.

We (along with Julian M. Whitaker, M.D., Pure Encapsulations, and the American Preventive Medical Association) have now sued the FDA for failure to comply with the court’s order that the four health claims in Pearson v. Shalala be approved with appropriate disclaimers; for violating our First Amendment rights; for violation of the Supremacy Clause (the Constitution is the supreme law of the land; executive agencies such as the FDA fall under the authority of Congress and the courts); and on the grounds that the FDA officials responsible for the FDA’s refusal to comply with the court’s decision have violated their oath of office (to uphold, defend, and protect the Constitution). You can download the entire suit (Case number 1:00CV00123, filed 1/19/00) from www.emord.com.

Among other things, this hard-hitting suit asks the district court to:

“Order in accordance with the Pearson Court’s constitutional mandate and the First Amendment that FDA authorize the B-Vitamin Health Claim [folic acid, B6, B12 may reduce the risk of cardiovascular disease] and the E-Vitamin Health Claims forthwith with such disclaimer or such disclaimers as are reasonably necessary to avoid a potentially misleading connotation in accordance with the requirements of the First Amendment as mandated by this Court in compliance with the decision of the United States Court of Appeals for the D.C. Circuit in Pearson v. Shalala. . . .” and to

“Order in accordance with 28. U.S.C. 1361 (to compel an officer of the United States to perform his duty) that FDA Commissioner Jane E. Henney, M.D.; FDA Director of the Center for Food Safety and Applied Nutrition Joseph A. Levitt; and FDA Director of the Office of Special Nutritionals Elizabeth A. Yetley, Ph.D. fulfill their constitutional duties by immediately authorizing the B-Vitamin Health Claim and the E-Vitamin Health Claims with such disclaimer or such disclaimers as are reasonably necessary to avoid a potentially misleading connotation in accordance with the requirements of the First Amendment as mandated by this Court in compliance with the decision of the United States Court of Appeals for the D.C. Circuit in Pearson v. Shalala. . . .” and to

“Order in accordance with this Court’s inherent judicial authority to ensure that its orders are implemented and 18 U.S.C. 401 that the Defendants FDA and FDA Commissioner Jane E. Henney, M.D. . . . Joseph A. Levitt . . . and Elizabeth A. Yetley, Ph.D. are in Contempt of Court for violating the Pearson Court’s constitutional mandate.” We encourage you to read the whole document. It will make you feel great to be a part of this. We are on our way to overthrowing the evil empire (well, one of the evil empires, anyway, since most of the other federal agencies are just as bad) and establishing a free market and free choice in medicine and helping re-establish the Constitution and the rule of law.”

POSSIBLE MECHANISM FOR PATHOLOGICAL CONSEQUENCES OF ELEVATED HOMOCYSTEINE LEVELS

Elevated homocysteine has been correlated with increased risks of cardiovascular disease and stroke, and homocysteine has been reported to be neurotoxic. One study even reported elevated homocysteine in cerebrospinal fluid of patients with fibromyalgia and chronic fatigue syndrome.¹ A newly described mechanism² may help explain the basis for some of these pathological effects.

The new study reports that, just as glucose can chemically combine with the amino acids in proteins to form glycosylated proteins (which are increased in diabetes and aging), homocysteine can also chemically combine with the amino acids in proteins to form another type of damaged proteins: homocysteinylated proteins. The authors propose that homocysteinylation is carried out by a nonenzymatic reaction (just as glycosylation is). Protein damage by homocysteinylation was measured in two enzymes, methionyl-tRNA synthetase and trypsin, which experienced a progressive loss in activity as the degree of homocysteinylation increased. Other proteins, such as myoglobin, cytochrome c, hemoglobin, fibrinogen, albumin, and gamma globulin, were shown to be denatured at various levels of homocysteinylation.

This damage is so undesirable that there is a special editing/proofreading mechanism in place to prevent the incorporation of homocysteine into proteins.  Homocysteine is converted to homocysteine thiolactone in this process. (There are also enzymatic reactions for converting homocysteine into methionine or cysteine that require folic acid, vitamin B6, and vitamin B12.) The new study reports that in human serum incubated with homocysteine thiolactone, protein homocysteinylation was a major reaction that could be observed with as little as 10 nmol of homocysteine thiolactone. The rate of the reaction was proportional to the lysine contained in the protein, as homocysteine thiolactone binds to lysine, producing a lysine-homocysteine adduct. (This may provide a basis for taking supplemental lysine, to soak up homocysteine thiolactone.)

The authors also proposed that homocysteinylation could lead to other forms of damage, such as increased unregulated disulfide (cross-linking) bonds in proteins, due to the incorporation of additional -SH (sulfhydryl) groups from the homocysteine. Another example is the production of hydrogen peroxide by the autooxidation of homocysteine (see below for deleterious effects of hydrogen peroxide on insulin signaling). The authors also note that a recent study reports that homocysteinylated LDL elicited an immune response in rabbits.

The authors speculate that macrophages attempting to ingest proteins damaged by homocysteinylation may cause damage to endothelial cells lining blood vessels, a possible explanation for at least part of homocysteine’s correlation with cardiovascular disease.

These new data may help explain increased health risks resulting from elevated homocysteine levels and support recommendations for supplements, especially folic acid, vitamin B6, and vitamin B12, to reduce homocysteine levels, the subject of one of our recent proposed health claims rejected and prohibited by the FDA.

References

1. Regland et al, “Increased Concentrations of Homocysteine in the Cerebrospinal Fluid in Patients with Fibromyalgia and Chronic Fatigue Syndrome,” Scand. J. Rheumatol. 26:301-7 (1997).
2. Jakubowski, “Protein Homocysteinylation: Possible Mechanism Underlying Pathological Consequences of Elevated Homocysteine Levels,” The FASEB Journal 13:2277-2283 (1999).

EUROPEAN COMMISSION INCREASES REGULATION OF HERBALS

Europe is moving to reduce access to herbals by European consumers. The European Commission (EC) has drawn up an amendment to existing legislation to provide for requiring the demonstration of safety and efficacy and the imposition of legally binding government-set quality standards and other rules that make the regulation of herbals more consistent with rules governing conventional drugs. This follows earlier regulations in many European countries, such as Norway and England, to dramatically limit access to vitamins and other dietary supplements by imposing restrictive new regulations. Wonder how long it will be until European diplomats are sending dietary supplements from the U.S. back in their diplomatic pouches, as some Soviet bigwigs did during the Cold War.

References

1. “EC Sets Tougher Rules for Herbals,” Chem. Mktg. Reporter, Jan. 10, 2000.

INSULIN SIGNALING IS INHIBITED BY HYDROGEN PEROXIDE

The insulin-regulating pathways may be involved in aging processes. A gene regulating an insulin-receptor-like molecule, daf-2, in nematodes increases the lifespan of the animals when it is mutated. Changes in the expression of genes regulating energy use and distribution are important in the effects of caloric restriction in mice and other animals. Decreases in insulin sensitivity are associated with cardiovascular disease, diabetes, obesity, and aging.

A new paper¹ finds evidence that insulin signaling can be inhibited by micromolar levels of hydrogen peroxide released during oxidative stress. The effects were studied in human embryonic kidney fibroblasts and in fibroblasts overexpressing the human insulin receptor (NIH-B cells).

Hydrogen peroxide is produced in response to insulin, which increases oxidative stress (one reason why elevated insulin levels are undesirable). The authors of this study suggest that the inhibitory effects of hydrogen peroxide on insulin signaling may be part of a feedback mechanism to terminate the insulin signal. They propose that hyperinsulinemia may cause premature termination of insulin signaling through increased production of hydrogen peroxide. This would add hydrogen peroxide to the growing list of free radicals and other oxidative stress inducers that play a key role in genetic regulatory mechanisms.

The researchers examined the effects of micromolar hydrogen peroxide on the reduced insulin signaling resulting from hyperglycemia and that of TNF-alpha (tumor necrosis factor alpha, a cytokine released by fat cells, among others, and another good reason to get rid of excess fat cells). Both manganese chloride (which mimics a function of superoxide dismutase) and catalase, an enzyme that catalyzes the conversion of hydrogen peroxide to oxygen and water, prevented the hydrogen peroxide-induced attenuation of insulin signaling. While catalase prevented the inhibitory effect of TNF-alpha completely, it had no effect on hyperglycemia-induced inhibition of insulin-receptor tyrosine phosphorylation.

[Glutathione peroxidase (a selenium-containing enzyme) was not studied in this research, but it also removes hydrogen peroxide, doing so by using the hydrogen peroxide to oxidize reduced glutathione to oxidized glutathione. The latter is then regenerated to reduced glutathione by glutathione reductase.]

Preincubation of the NIH-B cells with the specific tyrosine phosphatase inhibitor sodium orthovanadate (250 µmol, 30 min) abolished the inhibitory effect of hydrogen peroxide on insulin-receptor tyrosine phosphorylation. The latter appears to help explain why vanadate supplementation can improve insulin sensitivity.

References

1. Hansen et al, “Insulin Signaling Is Inhibited by Micromolar Concentrations of H2O2,” J. Biol. Chem. 274(35):25078-25084 (1999).

INSULIN-LIKE GROWTH FACTOR 1: PLEIOTROPIC EFFECTS

The expression of some genes is more favorable when it takes place in young animals than when it takes place after animals are older. The existence of differences in the effect of a gene’s expression depending upon where it acts or the time of its expression are called pleiotropic effects.

The effect of insulin-like growth factor-1 (IGF-1) looks more and more like a pleiotropic effect. In mammals, IGF-1, released in response to growth hormone, stimulates growth and wound healing. As mammals age, however, it appears that IGF-1 may increase the likelihood of developing cancer, because it increases cellular division. It is well known that mitogens, substances that increase cell division, can increase the risk of cancer simply because the more times a cell divides, the more chances there are for a mistake to take place that will result in loss of proliferative control. In older humans, elevated levels of IGF-1 have been reported to be associated with increased risks of prostate and breast cancer.

Thus, we find that IGF-1 is associated with retinopathy because it stimulates the neovascularization (excess formation of blood vessels in the retina) that underlies retinopathy. While it is obviously important to be able to grow new blood vessels in case of injury, in response to exercise, and during preadult growth and development, in the long run there may be a pathological downside of excessive growth of blood vessels in some places, such as the retina (retinopathy) or in tumors (angiogenesis).

With regard to calorically restricted mice, there has been a report¹ that the IGF-1 receptor density increases with age (as compared to no consistent changes in ad lib-fed animals with age), accompanied by a decrease in IGF-1 levels and an increase in growth-hormone release. IGF-1 levels increase in ad lib-fed aging mice and in aging humans, while growth-hormone release decreases with age.

The amplitude of growth-hormone secretory pulses decreases with age in ad lib-fed animals, and short-term caloric restriction in young animals also results in a decline in the amplitude of growth hormone.  However, in older caloric-restricted animals, growth-hormone pulses were similar to those in young ad lib-fed mice, with both the number of pulses of growth hormone and mean growth hormone concentrations increased substantially compared to older ad lib-fed mice. Apparently, there is a long-term adjustment that takes place in the growth hormone and IGF-1 axis in chronically calorically restricted mice so that, even with 40% less food (called “moderate caloric restriction” to distinguish it from outright starvation), the animals have greater protein synthesis, along with greater growth-hormone and lower IGF-1 levels.

Another study² reports that in 24 postmenopausal women aged 57 and older who had taken long-term estrogen replacement treatment (83% for ten years or more), there were higher growth-hormone levels and lower IGF-1 levels than in estrogen nonusers. The long-term estrogen users had higher mean circulating GH levels and more frequent GH secretory bursts (though the amplitude of the GH bursts was no greater than in the nonusers), along with lower IGF-1 levels. All hormone users were taking 0.625 mg a day of Premarin for at least three years prior to the study. Whether the higher GH/lower IGF-1 has similar youth-promoting implications to the higher GH/lower IGF-1 of caloric restriction is something we don’t know. It should be noted that the decrease in IGF-1 levels was specific to oral estrogen replacement therapy (ERT) and did not apply to transdermal ERT. The authors state that oral but not transdermal ERT results in high liver-portal estrogen concentrations, and estrogen inhibits liver IGF-1 synthesis. Hence, the lower IGF-1 levels may be a direct effect on the liver.

References

1. Sonntag et al, “Pleiotropic Effects of Growth Hormone and Insulin-like Growth Factor (IGF-1) on Biological Aging: Inferences from Moderate Caloric-Restricted Animals,” J. Gerontol.: Biological Sciences 54A(12):B521-B538 (1999).
2. Moe et al, “Growth Hormone in Postmenopausal Women After Long-Term Oral Estrogen Replacement Therapy,” J. Gerontol.: Biological Sciences 53A(2):B117-B124 (1998).

CHEWING THE FAT: INCREASING ENERGY EXPENDITURE
TO REDUCE BODY FAT

A letter in the 30 December 1999 New England Journal of Medicine suggests an unusual way to speed up fat loss:  chewing gum. The authors note that in cows, chewing increases energy expenditure by approximately 20%. Cows spend about eight hours a day chewing their cud, that is, slowly and carefully grinding food that is initially quickly swallowed and stored in a special storage stomach and later regurgitated for chewing. According to measurements made by the authors, people can increase energy expenditure by about 19% by a lot of chewing (no regurgitation required).

Measurements were made in seven nonobese human subjects with stable weight while seated at rest with their arms and legs supported (so that energy expenditure could be attributed to the chewing).  After ascertaining energy expenditure for 30 minutes at rest, the subjects were given 8.4 grams of calorie-free gum and instructed to chew at a frequency of precisely 100 Hz with the aid of a metronome. (This would require the subjects to chew 100 times a second, so this has to be an error; we assume that the subjects were instructed to chew 100 times a minute.)  After 12 minutes, the gum was removed and energy expenditure measured for the 12 minutes after chewing. The results showed that chewing gum led to a mean increase in energy expenditure of 19 +4 percent above baseline values. (To put things into perspective, standing was associated in the same subjects with a mean increase in energy expenditure of 11 + 11 percent, and walking at one mile per hour with an increase of 106 + 26 percent above baseline values.)

The authors summed up by saying that, if a person chewed gum during waking hours and changed no other components of energy balance, a yearly loss of more than 5 kg of body fat might be anticipated.

1. Levine et al, “The Energy Expended in Chewing Gum,” N.Engl.J.Med. pg. 2100, 30 Dec. 1999.

MARIJUANA IN THE NEWS: INCREASE IN RIGHT-HEMISPHERE BLOOD FLOW REPORTED

A study by scientists at the Duke University Medical Center in Durham, North Carolina, reports that cerebral blood flow showed an overall increase (most marked in the right hemisphere, frontal lobes, and anterior cingulate). The measurements were made after IV infusions of tetrahydrocannabinol in 59 normal, right-handed volunteers. We remember research from 30 years or so ago that was done at UCLA, reporting an increase in right-hemisphere activity following the use of marijuana by student volunteers.  The improved blood flow might account, at least in part, for the increased creativity (associational, parallel, or lateral thinking) some people have reported when they use marijuana.

1. Abstract in CA Selects: Psychobiochemistry (issue 1, 2000): Mathew et al, “Regional Cerebral Blood Flow and Depersonalization After Tetrahydrocannabinol Administration,” Acta. Psychiatr. Scand. 100(1):67-75

This newsletter is written by scientists Durk Pearson & Sandy Shaw^® for other scientists studying aging and for interested physicians and laypersons, as well as for lawyers interested in promoting medical freedom of choice and Constitutional government. The information provided here is not intended as a replacement for professional medical or legal advice.

FDA UPDATE: FDA’S TEN-YEAR PLAN 

The FDA’s newly announced Ten-Year Plan for Dietary Supplement Strategy is a real laugh. (Those who want to read the whole thing can download it at http://vm.cfsan.fda.gov/~dms/) The FDA states, as the goal of its Ten-Year Plan, that, by the year 2010, it will have established a “science-based regulatory program that fully implements the Dietary Supplement Health and Education Act of 1994.” So  it only takes them (if they meet their “goal”) sixteen years to implement the DSHEA.

Many of the items listed in the Ten-Year Plan as subgoals, such as defining the difference between a dietary supplement and a drug and defining when a disease claim for a dietary supplement becomes a drug claim, are issues that have already been decided in the relevant congressional statute (DSHEA) that determines the extent of FDA authority over dietary supplements. The classes of substances that qualify as dietary supplements are explicitly given in the DSHEA, which also makes it clear that a truthful statement of a substance-disease relationship about a dietary supplement is not to be regulated as a drug claim.

FDA also proposes to “clarify” the regulation of a “dual status” product, which is a substance that is used both as a drug and as a dietary supplement. An example is beta-carotene, which is used as a drug (at high dose levels) in the treatment of xeroderma pigmentosum and which is, of course, also a dietary supplement.  However, there is nothing for the FDA to “clarify,” since beta-carotene qualifies as a dietary supplement under the DSHEA. Presumably, what the FDA hopes to do is to prohibit sellers of dietary-supplement beta-carotene from letting consumers know how beta-carotene is also used as a drug. If a company could simply sell beta-carotene while providing truthful information about its use at high dose levels for treating xeroderma pigmentosum, who would be interested in getting FDA approval to sell beta-carotene as a drug? Yes, this is a problem for the FDA, but we do not see how the communication of such information can be prohibited without being in violation of the First Amendment.

FDA FINALIZES ITS RULES ON STRUCTURE-FUNCTION CLAIMS FOR DIETARY SUPPLEMENTS 

The FDA has decided what it will allow as “structure-function” claims, non-disease claims that, under a provision of the DSHEA, may be provided on labels and in advertisements for dietary supplements without getting FDA’s preapproval. “Health claims,” which convey information on supplement-disease relationships, require FDA preapproval. However, under the court ruling in Pearson v. Shalala (see www.emord.com for the entire text of the ruling), the FDA may prohibit only health claims that are “inherently misleading” (i.e., false) and must approve the remaining claims, with reasonable disclaimers if FDA considers them necessary to avoid consumer misinterpretation.

FDA has now “clarified” the “structure-function” claims that are allowed without its approval under the DSHEA. (Another way to look at it is that “structure-function” claims are preapproved by Congress, hence you don’t need to get FDA approval, since the Congress’s authority is above that of an executive agency.)

The FDA, in fifty pages of detailed instructions and examples, has confused the issue totally. For example, the FDA says you can point out that a supplement “helps maintain a healthy cholesterol level,” but you  can’t say that a supplement helps prevent an unhealthy cholesterol level, such as by reducing it. The FDA says that the latter statement would suggest prevention of a disease, while the former wouldn’t. Right. One severe problem with this is that one may wonder what the meaning of “helps maintain a healthy cholesterol level” can possibly be if it can’t mean that the supplement may reduce cholesterol levels or, to put it another way, may prevent a rise in cholesterol levels. The reason for this strange interpretation by FDA is that, even if diseases are not mentioned explicitly in a structure-function claim, a consumer might recognize the implication of a structure-function in relation to a disease. For example, one might recognize a claim that an antioxidant supplement reduces the risk of LDL oxidation as a claim about the possible reduction of the risk of atherosclerosis. Hence, FDA is trying to eliminate all structure-function claims where somebody might infer an effect of the supplement on a disease. This is, of course, the category into which nearly all the interesting structure-function claims are likely to fall and thus be converted by FDA to “health claims,” which require FDA preapproval.

The structure-function rules are a tissue of First Amendment violations. An interesting part of the rule is the FDA’s analysis of how and whether the First Amendment applies to their structure-function rules.  (We were told by Jonathan Emord that a lawyer working at the FDA told him that until the court decision in Pearson v. Shalala, the FDA did not even know that the First Amendment applied to them!!)

The FDA cites early court decisions in commercial speech jurisprudence, such as Central Hudson and the Virginia State Board of Pharmacy, rather than the newer court decisions that have displaced them, such as 44Liquormart, Coors, and Pearson v. Shalala, in which commercial speech is given strong First Amendment support. For example, in the decision in Central Hudson, the U.S. Supreme Court held that “commercial speech is such a sturdy brand of expression that traditional prior restraint doctrine may not apply to it,” a view that is not favored in the courts any longer.

The FDA states that prior restraints on truthful speech are allowed for substances for which the FDA has not approved safety and efficacy. The DSHEA grants FDA no such authority, nor could it in the first place, because the First Amendment trumps congressional statute. In fact, the DSHEA stated that neither dietary supplements nor dietary supplement health claims may be regulated as if they were drugs.  Dietary supplements are not required to pass FDA tests for safety and efficacy. The FDA does have safety authority, but the burden of proof is on them if they wish to remove something from the market as unsafe.  The court ruling in Pearson v. Shalala made it clear that where speech is truthful, FDA may not prohibit it outright, but may require disclaimers to clarify potentially misleading statements.

Possibly the biggest laugh in the whole of FDA’s First Amendment analysis is their claim that: “As a government agency with no financial stake in either permitting or denying claims, FDA is in a position to evaluate the strength of the safety and efficacy evidence objectively.” The facts strongly suggest otherwise. The FDA receives close to a billion dollars a year from pharmaceutical companies as “users’ fees.” If the FDA cannot protect the market for FDA-approved drugs going through the long and expensive FDA process, then pharmaceutical companies may decide their “users’ fees” are a waste of their money. Hence, the FDA has a huge financial stake in “either permitting or denying” health claims for dietary supplements in competition with pharmaceutical drugs.

Finally, and most astonishingly, the FDA boldly rejects the court’s decision in Pearson v. Shalala, declaring itself to be above the legislative and judiciary branches of the federal government and, indeed, above the Constitution itself! The FDA says that having to [as the court ruled] permit all health claims but those that are inherently misleading (i.e., false), though the FDA can require disclaimers when reasonably necessary to prevent potentially misleading connotations of health claims, would be “untenable,” since companies could avoid the time and expenses of complying with new drug regulations by merely attaching a disclaimer to a disease treatment or prevention claim, and – you better grab your hanky – “the long-standing system of drug regulation in this country would be eviscerated.” A few comments on this performance: First, one of the clearly stated purposes of the DSHEA was to allow manufacturers and marketers of dietary supplements to avoid “the time and expenses of complying with new drug regulations” in the communication of truthful information about supplements. Second, the First Amendment trumps any “long-standing system of drug regulation.” Finally, the FDA cries wolf, since most pharmaceutical drugs would not qualify as dietary supplements, hence those unfortunates manufacturing and marketing them will still have to comply with FDA’s drug regulations. Perhaps they are concerned about investment money flowing into dietary supplements rather than prescription drugs. . . .

The FDA pulls out the worn, old argument that the average consumer “does not possess the medical and scientific expertise necessary to evaluate claims about the effect of a product on disease.” The First Amendment does not permit the government to prohibit the communication of complex, hard-to-understand, but truthful, information. Let the FDA provide counterinformation.

MORE SUITS TO COME – YOU CAN HELP 

We close this section by noting that a group of us are continuing to attack the FDA in the courts (see the following for more). If you would like to help the two of us pay our share of the mounting legal bills, please send a donation for the Pearson & Shaw Litigation Fund to Emord & Associates, 5282 Lyngate Ct., Burke, VA 22015. We appreciate your help and encouragement.

NEW LAWSUIT UPS THE ANTE AS FDA CONTINUES TO STONEWALL 

One year after the January 15, 1999 landmark decision in Pearson v. Shalala in which the Court of Appeals for the District of Columbia Circuit ruled 3-0 (appeal for rehearing en banc turned down 11-0; not appealed to the U.S. Supreme Court) that the FDA’s health-claims approval process violated the First Amendment of the United States Constitution, the FDA has not complied with the court’s order. The court ruled that the FDA had to approve all health claims that were not “inherently misleading” (i.e., false), but could require disclaimers if the agency thought that was reasonably necessary to prevent potentially misleading conclusions by consumers.

In the year since then, the FDA has not approved any of the four health claims that were the subject of Pearson v. Shalala and has rejected two additional proposed health claims filed by a group of us: one that folic acid, vitamin B6, and vitamin B12 may reduce the risk of cardiovascular disease, and the other that vitamin E may reduce the risk of cardiovascular disease.  FDA has refused to implement the Pearson court decision’s disclaimer approach to potentially misleading health claims, but continues to prohibit them outright.

We (along with Julian M. Whitaker, M.D., Pure Encapsulations, and the American Preventive Medical Association) have now sued the FDA for failure to comply with the court’s order that the four health claims in Pearson v. Shalala be approved with appropriate disclaimers; for violating our First Amendment rights; for violation of the Supremacy Clause (the Constitution is the supreme law of the land; executive agencies such as the FDA fall under the authority of Congress and the courts); and on the grounds that the FDA officials responsible for the FDA’s refusal to comply with the court’s decision have violated their oath of office (to uphold, defend, and protect the Constitution). You can download the entire suit (Case number 1:00CV00123, filed 1/19/00) from www.emord.com.

Among other things, this hard-hitting suit asks the district court to:

“Order in accordance with the Pearson Court’s constitutional mandate and the First Amendment that FDA authorize the B-Vitamin Health Claim [folic acid, B6, B12 may reduce the risk of cardiovascular disease] and the E-Vitamin Health Claims forthwith with such disclaimer or such disclaimers as are reasonably necessary to avoid a potentially misleading connotation in accordance with the requirements of the First Amendment as mandated by this Court in compliance with the decision of the United States Court of Appeals for the D.C. Circuit in Pearson v. Shalala. . . .” and to

“Order in accordance with 28. U.S.C. 1361 (to compel an officer of the United States to perform his duty) that FDA Commissioner Jane E. Henney, M.D.; FDA Director of the Center for Food Safety and Applied Nutrition Joseph A. Levitt; and FDA Director of the Office of Special Nutritionals Elizabeth A. Yetley, Ph.D. fulfill their constitutional duties by immediately authorizing the B-Vitamin Health Claim and the E-Vitamin Health Claims with such disclaimer or such disclaimers as are reasonably necessary to avoid a potentially misleading connotation in accordance with the requirements of the First Amendment as mandated by this Court in compliance with the decision of the United States Court of Appeals for the D.C. Circuit in Pearson v. Shalala. . . .” and to

“Order in accordance with this Court’s inherent judicial authority to ensure that its orders are implemented and 18 U.S.C. 401 that the Defendants FDA and FDA Commissioner Jane E. Henney, M.D. . . . Joseph A. Levitt . . . and Elizabeth A. Yetley, Ph.D. are in Contempt of Court for violating the Pearson Court’s constitutional mandate.” We encourage you to read the whole document. It will make you feel great to be a part of this. We are on our way to overthrowing the evil empire (well, one of the evil empires, anyway, since most of the other federal agencies are just as bad) and establishing a free market and free choice in medicine and helping re-establish the Constitution and the rule of law.”

POSSIBLE MECHANISM FOR PATHOLOGICAL CONSEQUENCES OF ELEVATED HOMOCYSTEINE LEVELS

Elevated homocysteine has been correlated with increased risks of cardiovascular disease and stroke, and homocysteine has been reported to be neurotoxic. One study even reported elevated homocysteine in cerebrospinal fluid of patients with fibromyalgia and chronic fatigue syndrome.¹ A newly described mechanism² may help explain the basis for some of these pathological effects.

The new study reports that, just as glucose can chemically combine with the amino acids in proteins to form glycosylated proteins (which are increased in diabetes and aging), homocysteine can also chemically combine with the amino acids in proteins to form another type of damaged proteins: homocysteinylated proteins. The authors propose that homocysteinylation is carried out by a nonenzymatic reaction (just as glycosylation is). Protein damage by homocysteinylation was measured in two enzymes, methionyl-tRNA synthetase and trypsin, which experienced a progressive loss in activity as the degree of homocysteinylation increased. Other proteins, such as myoglobin, cytochrome c, hemoglobin, fibrinogen, albumin, and gamma globulin, were shown to be denatured at various levels of homocysteinylation.

This damage is so undesirable that there is a special editing/proofreading mechanism in place to prevent the incorporation of homocysteine into proteins.  Homocysteine is converted to homocysteine thiolactone in this process. (There are also enzymatic reactions for converting homocysteine into methionine or cysteine that require folic acid, vitamin B6, and vitamin B12.) The new study reports that in human serum incubated with homocysteine thiolactone, protein homocysteinylation was a major reaction that could be observed with as little as 10 nmol of homocysteine thiolactone. The rate of the reaction was proportional to the lysine contained in the protein, as homocysteine thiolactone binds to lysine, producing a lysine-homocysteine adduct. (This may provide a basis for taking supplemental lysine, to soak up homocysteine thiolactone.)

The authors also proposed that homocysteinylation could lead to other forms of damage, such as increased unregulated disulfide (cross-linking) bonds in proteins, due to the incorporation of additional -SH (sulfhydryl) groups from the homocysteine. Another example is the production of hydrogen peroxide by the autooxidation of homocysteine (see below for deleterious effects of hydrogen peroxide on insulin signaling). The authors also note that a recent study reports that homocysteinylated LDL elicited an immune response in rabbits.

The authors speculate that macrophages attempting to ingest proteins damaged by homocysteinylation may cause damage to endothelial cells lining blood vessels, a possible explanation for at least part of homocysteine’s correlation with cardiovascular disease.

These new data may help explain increased health risks resulting from elevated homocysteine levels and support recommendations for supplements, especially folic acid, vitamin B6, and vitamin B12, to reduce homocysteine levels, the subject of one of our recent proposed health claims rejected and prohibited by the FDA.

References

1. Regland et al, “Increased Concentrations of Homocysteine in the Cerebrospinal Fluid in Patients with Fibromyalgia and Chronic Fatigue Syndrome,” Scand. J. Rheumatol. 26:301-7 (1997).
2. Jakubowski, “Protein Homocysteinylation: Possible Mechanism Underlying Pathological Consequences of Elevated Homocysteine Levels,” The FASEB Journal 13:2277-2283 (1999).

EUROPEAN COMMISSION INCREASES REGULATION OF HERBALS

Europe is moving to reduce access to herbals by European consumers. The European Commission (EC) has drawn up an amendment to existing legislation to provide for requiring the demonstration of safety and efficacy and the imposition of legally binding government-set quality standards and other rules that make the regulation of herbals more consistent with rules governing conventional drugs. This follows earlier regulations in many European countries, such as Norway and England, to dramatically limit access to vitamins and other dietary supplements by imposing restrictive new regulations. Wonder how long it will be until European diplomats are sending dietary supplements from the U.S. back in their diplomatic pouches, as some Soviet bigwigs did during the Cold War.

References

1. “EC Sets Tougher Rules for Herbals,” Chem. Mktg. Reporter, Jan. 10, 2000.

INSULIN SIGNALING IS INHIBITED BY HYDROGEN PEROXIDE

The insulin-regulating pathways may be involved in aging processes. A gene regulating an insulin-receptor-like molecule, daf-2, in nematodes increases the lifespan of the animals when it is mutated. Changes in the expression of genes regulating energy use and distribution are important in the effects of caloric restriction in mice and other animals. Decreases in insulin sensitivity are associated with cardiovascular disease, diabetes, obesity, and aging.

A new paper¹ finds evidence that insulin signaling can be inhibited by micromolar levels of hydrogen peroxide released during oxidative stress. The effects were studied in human embryonic kidney fibroblasts and in fibroblasts overexpressing the human insulin receptor (NIH-B cells).

Hydrogen peroxide is produced in response to insulin, which increases oxidative stress (one reason why elevated insulin levels are undesirable). The authors of this study suggest that the inhibitory effects of hydrogen peroxide on insulin signaling may be part of a feedback mechanism to terminate the insulin signal. They propose that hyperinsulinemia may cause premature termination of insulin signaling through increased production of hydrogen peroxide. This would add hydrogen peroxide to the growing list of free radicals and other oxidative stress inducers that play a key role in genetic regulatory mechanisms.

The researchers examined the effects of micromolar hydrogen peroxide on the reduced insulin signaling resulting from hyperglycemia and that of TNF-alpha (tumor necrosis factor alpha, a cytokine released by fat cells, among others, and another good reason to get rid of excess fat cells). Both manganese chloride (which mimics a function of superoxide dismutase) and catalase, an enzyme that catalyzes the conversion of hydrogen peroxide to oxygen and water, prevented the hydrogen peroxide-induced attenuation of insulin signaling. While catalase prevented the inhibitory effect of TNF-alpha completely, it had no effect on hyperglycemia-induced inhibition of insulin-receptor tyrosine phosphorylation.

[Glutathione peroxidase (a selenium-containing enzyme) was not studied in this research, but it also removes hydrogen peroxide, doing so by using the hydrogen peroxide to oxidize reduced glutathione to oxidized glutathione. The latter is then regenerated to reduced glutathione by glutathione reductase.]

Preincubation of the NIH-B cells with the specific tyrosine phosphatase inhibitor sodium orthovanadate (250 µmol, 30 min) abolished the inhibitory effect of hydrogen peroxide on insulin-receptor tyrosine phosphorylation. The latter appears to help explain why vanadate supplementation can improve insulin sensitivity.

References

1. Hansen et al, “Insulin Signaling Is Inhibited by Micromolar Concentrations of H2O2,” J. Biol. Chem. 274(35):25078-25084 (1999).

INSULIN-LIKE GROWTH FACTOR 1: PLEIOTROPIC EFFECTS

The expression of some genes is more favorable when it takes place in young animals than when it takes place after animals are older. The existence of differences in the effect of a gene’s expression depending upon where it acts or the time of its expression are called pleiotropic effects.

The effect of insulin-like growth factor-1 (IGF-1) looks more and more like a pleiotropic effect. In mammals, IGF-1, released in response to growth hormone, stimulates growth and wound healing. As mammals age, however, it appears that IGF-1 may increase the likelihood of developing cancer, because it increases cellular division. It is well known that mitogens, substances that increase cell division, can increase the risk of cancer simply because the more times a cell divides, the more chances there are for a mistake to take place that will result in loss of proliferative control. In older humans, elevated levels of IGF-1 have been reported to be associated with increased risks of prostate and breast cancer.

Thus, we find that IGF-1 is associated with retinopathy because it stimulates the neovascularization (excess formation of blood vessels in the retina) that underlies retinopathy. While it is obviously important to be able to grow new blood vessels in case of injury, in response to exercise, and during preadult growth and development, in the long run there may be a pathological downside of excessive growth of blood vessels in some places, such as the retina (retinopathy) or in tumors (angiogenesis).

With regard to calorically restricted mice, there has been a report¹ that the IGF-1 receptor density increases with age (as compared to no consistent changes in ad lib-fed animals with age), accompanied by a decrease in IGF-1 levels and an increase in growth-hormone release. IGF-1 levels increase in ad lib-fed aging mice and in aging humans, while growth-hormone release decreases with age.

The amplitude of growth-hormone secretory pulses decreases with age in ad lib-fed animals, and short-term caloric restriction in young animals also results in a decline in the amplitude of growth hormone.  However, in older caloric-restricted animals, growth-hormone pulses were similar to those in young ad lib-fed mice, with both the number of pulses of growth hormone and mean growth hormone concentrations increased substantially compared to older ad lib-fed mice. Apparently, there is a long-term adjustment that takes place in the growth hormone and IGF-1 axis in chronically calorically restricted mice so that, even with 40% less food (called “moderate caloric restriction” to distinguish it from outright starvation), the animals have greater protein synthesis, along with greater growth-hormone and lower IGF-1 levels.

Another study² reports that in 24 postmenopausal women aged 57 and older who had taken long-term estrogen replacement treatment (83% for ten years or more), there were higher growth-hormone levels and lower IGF-1 levels than in estrogen nonusers. The long-term estrogen users had higher mean circulating GH levels and more frequent GH secretory bursts (though the amplitude of the GH bursts was no greater than in the nonusers), along with lower IGF-1 levels. All hormone users were taking 0.625 mg a day of Premarin for at least three years prior to the study. Whether the higher GH/lower IGF-1 has similar youth-promoting implications to the higher GH/lower IGF-1 of caloric restriction is something we don’t know. It should be noted that the decrease in IGF-1 levels was specific to oral estrogen replacement therapy (ERT) and did not apply to transdermal ERT. The authors state that oral but not transdermal ERT results in high liver-portal estrogen concentrations, and estrogen inhibits liver IGF-1 synthesis. Hence, the lower IGF-1 levels may be a direct effect on the liver.

References

1. Sonntag et al, “Pleiotropic Effects of Growth Hormone and Insulin-like Growth Factor (IGF-1) on Biological Aging: Inferences from Moderate Caloric-Restricted Animals,” J. Gerontol.: Biological Sciences 54A(12):B521-B538 (1999).
2. Moe et al, “Growth Hormone in Postmenopausal Women After Long-Term Oral Estrogen Replacement Therapy,” J. Gerontol.: Biological Sciences 53A(2):B117-B124 (1998).

CHEWING THE FAT: INCREASING ENERGY EXPENDITURE
TO REDUCE BODY FAT

A letter in the 30 December 1999 New England Journal of Medicine suggests an unusual way to speed up fat loss:  chewing gum. The authors note that in cows, chewing increases energy expenditure by approximately 20%. Cows spend about eight hours a day chewing their cud, that is, slowly and carefully grinding food that is initially quickly swallowed and stored in a special storage stomach and later regurgitated for chewing. According to measurements made by the authors, people can increase energy expenditure by about 19% by a lot of chewing (no regurgitation required).

Measurements were made in seven nonobese human subjects with stable weight while seated at rest with their arms and legs supported (so that energy expenditure could be attributed to the chewing).  After ascertaining energy expenditure for 30 minutes at rest, the subjects were given 8.4 grams of calorie-free gum and instructed to chew at a frequency of precisely 100 Hz with the aid of a metronome. (This would require the subjects to chew 100 times a second, so this has to be an error; we assume that the subjects were instructed to chew 100 times a minute.)  After 12 minutes, the gum was removed and energy expenditure measured for the 12 minutes after chewing. The results showed that chewing gum led to a mean increase in energy expenditure of 19 +4 percent above baseline values. (To put things into perspective, standing was associated in the same subjects with a mean increase in energy expenditure of 11 + 11 percent, and walking at one mile per hour with an increase of 106 + 26 percent above baseline values.)

The authors summed up by saying that, if a person chewed gum during waking hours and changed no other components of energy balance, a yearly loss of more than 5 kg of body fat might be anticipated.

1. Levine et al, “The Energy Expended in Chewing Gum,” N.Engl.J.Med. pg. 2100, 30 Dec. 1999.

MARIJUANA IN THE NEWS: INCREASE IN RIGHT-HEMISPHERE BLOOD FLOW REPORTED

A study by scientists at the Duke University Medical Center in Durham, North Carolina, reports that cerebral blood flow showed an overall increase (most marked in the right hemisphere, frontal lobes, and anterior cingulate). The measurements were made after IV infusions of tetrahydrocannabinol in 59 normal, right-handed volunteers. We remember research from 30 years or so ago that was done at UCLA, reporting an increase in right-hemisphere activity following the use of marijuana by student volunteers.  The improved blood flow might account, at least in part, for the increased creativity (associational, parallel, or lateral thinking) some people have reported when they use marijuana.

1. Abstract in CA Selects: Psychobiochemistry (issue 1, 2000): Mathew et al, “Regional Cerebral Blood Flow and Depersonalization After Tetrahydrocannabinol Administration,” Acta. Psychiatr. Scand. 100(1):67-75

HAPPY 2000! STICK AROUND.
THE BEST OF LIFE EXTENSION IS YET TO COME!

LOOKING AHEAD-LIFE EXTENSION: 2000 AND BEYOND
THE FUTURE OF LIFE EXTENSION IS LOOKING GREAT! KEEP YOURSELF IN GOOD HEALTH SO YOU CAN TAKE ADVANTAGE OF SOME OF THE UPCOMING OPPORTUNITIES . . .

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GLUCOWATCH

A new medical device promises a major breakthrough in practical life extension, as well as in the treatment of serious diseases such as diabetes. The device, called the GlucoWatch (Cygnus, Inc., 400 Penobscot Dr., Redwood City, CA 94063, Attn.: Russell O. Potts, Ph.D.), was described in an article in the November 17, 1999 Journal of the American Medical Association. As the name suggests, the device measures blood glucose by means of a painless, automatic, and noninvasive method while the user wears it on his/her wrist like a watch. The device is said to provide up to three readings per hour for as long as 12 hours after a single blood glucose measurement (using finger-stick blood sample) for calibration.

The device extracts glucose through the skin using an applied potential (a process known as iontophoresis) and measures the extracted sample using an electrochemical-enzymatic sensor. The electro-osmotic flow causes glucose to be transported across the skin. A single-point calibration (taken with – OUCH – a finger-stick blood sample) compensates for the variability in the amount of glucose extracted compared with blood glucose in individuals and at skin sites. The results of a study using five subjects with diabetes in twelve uses showed a mean correlation (between glucose extracted and blood glucose) coefficient of 0.89 and a mean absolute error of 13%. Full details of how the device works are contained in the JAMA article.

The potential for this device in the design of practical life extension programs is immense. A well-known hypothesis proposes that a low-glycemic-index diet (one that does not increase blood glucose excessively) is likely to have beneficial health and possibly even life-extending effects. It is well known that high blood glucose levels (even temporarily following a high-carbohydrate meal) promote glycation¹ (cross linking between sugars and proteins), obesity, and increased oxidative stress,² among other things.

LOW-GLYCEMIC-INDEX DIET BECOMES PRACTICAL
As noted in a comment on a recent review,³ a low-glycemic-index diet is very difficult to follow because of several factors, including the lack of availability of data on the glycemic indices of individual foods and of mixed meals. Also, the comment notes that “in the determination of glycemic index, there are no widely practiced standards regarding food preparation, cooking, storage . . . .” Thus, even the available data are difficult to use. The GlucoWatch virtually eliminates these problems by making it possible to painlessly follow one’s blood sugar levels directly. Hence, each individual user can establish the best dietary practices for himself or herself, with data that relate blood sugar levels to diet, time of day, stress conditions, and so forth.

Furthermore, one can quickly test the effects of various dietary supplements (such as those containing various fibers, a range of doses of lipoic acid, vitamin E, chromium, ethyl alcohol, and so forth) to determine how they affect blood sugar levels. The development of better formulations to keep blood sugar levels in a desired range will accelerate. It will likely soon be possible for people to eat nearly any desired foods (even sweet desserts) without having surges in blood sugar levels (which may help to prevent obesity) and to do so without pain, fear, or guilt. And no longer will you have to use measurements made by other people, as you can do your own with the GlucoWatch and devices to follow.

DNA GENE ARRAYS FOR LIFE EXTENSION
As many of you may know, there has already been a study published using a gene array to simultaneously monitor the expression of 6,347 genes (representing, the authors estimate, 5% to 10% of the mouse genome) in gastrocnemius [calf] muscle of calorically restricted mice (76% of calories fed to controls) as compared to controls.⁴The idea was to pinpoint those genes that had their expression markedly reduced or increased by caloric restriction to focus on genes responsible for the life-extending effects of the diet on mice. Examples of their many findings were: Of those genes whose age-associated expression was changed the most (twofold or greater increase or decrease), 29% were completely prevented by caloric restriction (CR), while another 34% were partially prevented by CR. CR resulted in the induction of 51 genes (1.8-fold or larger) as compared with the age-matched control animals. CR-induced genes were involved in energy metabolism, stress response, and DNA-repair pathways. The authors suggest that some of the observed gene changes may be the basis for the metabolic shift toward increased biosynthesis and macromolecular turnover seen in CR animals. “A hormonal trigger for this shift may be an alteration in the insulin-signaling pathway through increased expression of genes that mediate insulin sensitivity, a finding that links our observations to those obtained through the genetic analysis of aging in the nematode C. elegans [see Figure 1].” This is the first of a series of publications these authors plan to make on the basis of their analysis. They have also begun collecting data for a study of gene-expression changes in muscle of Rhesus monkeys of different ages and various degrees of caloric restriction, using a human gene-array chip. Richard Weindruch, one of the researchers, stated: “Technically, there will be the concern about the human chip not working for the Rhesus monkey, which is ‘only’ 95-97% genetically similar to humans. We think, however, that probably won’t be a problem, at least for many of the genes that may be most important, and those are the ancient, highly conserved kinds of molecules, such as heat-shock factors and the like . . . .”⁵ WOW!

Figure 1. The nematode C. elegans in reproductive embrace.

Another gene-array study was recently reported⁶ that detected changes in gene expression that took place in prostate cancer cells as they progressed from androgen-dependent to androgen-independent. The study found, for example, that insulin-like growth-factor-binding protein 2 and HSP27, a heat-shock protein, were the most consistently overexpressed in the hormone-refractory tumor cells. Studies like this will have a major impact on how cancer is treated.

FUTURE STUDIES USING GENE ARRAYS
DNA gene-array technology has just become available, of course, and the implications for health and life extension are immense. Using this new technology, for example, studies could determine changes in gene expression using methyl-donor dietary supplements. Methylation is a major biological method of regulating gene expression, with methylation generally silencing genes. It is thought that some early cancers may involve hypomethylation,⁷ a deficiency in methylation. It is possible that this could be prevented by increasing consumption of methyl donors such as choline and betaine, along with necessary cofactors such as folic acid and vitamin B12. This can be tested using the new technology.

Other gene-array studies could locate major changes in gene expression that arise from exercise compared to nonactivity, possibly leading to the development of a dietary supplement that can be demonstrated to provide at least some of the benefits of exercise. Researchers could look at gene expression in obese versus lean subjects, testing potential weight-loss formulations for their ability to make obese subjects express genes more like lean subjects.

The ability of DNA gene arrays to analyze and make sense of data is dependent upon silicon technology, and silicon technology is doubling such abilities every 18 months! New medicines, medical devices, and longer life span are about to explode into the marketplace, along with the inevitable authoritarian discussions by supposed ethicists (more ethical than you and me) about inequality in the receipt of information and medical care. For example, should you be allowed to buy this new medical technology with your own money or should government “experts” decide how you can spend your own money? Should anybody be allowed to increase his or her own life span when there are starving people in Africa? These are not silly questions. They will be asked with the utmost seriousness by people who do not think you own your own life and who are willing to use the guns of the government to manipulate your life or even to take it in the pursuit of their own agenda.

GENE-CONTROLLING MAMMALIAN LIFE SPAN IDENTIFIED
In the meantime, using a different method (not a gene array), a group of scientists has identified a gene, p66^shc, that induced stress resistance and increased life span by 30% in mice in which the gene was mutated to decrease its function or ablated to eliminate it.⁸ The scientists studied the role of p66^shc in stress responses by measuring the extent of its tyrosine phosphorylation when mouse-embryo fibroblasts were treated with ultraviolet light, hydrogen peroxide, or epidermal growth factor. Ablation of the gene increased resistance of the fibroblasts to hydrogen peroxide to less than 30% cell death.

The cells that survived this stress maintained their proliferative potential. Similar results were obtained with ultraviolet treatment. In the wild-type (normal gene) fibroblasts, about 80% and 40% of the cells survived after one and two days of treatment, whereas in the cells with ablated p66^shc, the cytotoxic effect of UV was negligible. The authors suggest that p66^shc is a critical component of the apoptotic (programmed cell death) response to oxidative damage, whereas it has no effect on the arrest of cell proliferation induced by DNA damage.

Clearly, we are fast approaching a time when human gene therapy will be able to deliver longer life span and improvements in mental and physical function, as well as (but not merely for) the treatment of disease. This will have bewildering results for many whose philosophies require stability and maintenance of the biological status quo of both humans and the world in which we live. For example, widespread genetic modification could scramble the identity of racial groups, since each is by definition a group that shares certain genetically determined phenotypic traits. The increasing use of genetic modification of plant and animal life (including the upcoming cloning of “extinct” species such as mammoths) will destroy the idea of a single environmental ideal (e.g., the parochial snapshot that exists at exactly this moment) that must be protected from change at all cost.

Genetic modification will increase human inequality (i.e., diversity) by permitting humans to increase their genetic choices beyond those made available by evolutionary processes. People who have a low tolerance for differences in others may be in for a shock. Of course, there is always Prozac^® . . . .

References

1. See, for example, Paul and Bailey, – Glycation of Collagen: The Basis of its Central Role in the Late Complications of Ageing and Diabetes,- Int. J. Biochem. Cell Biol. 28(12):1297-1310 (1996).
2. See, for example, VERIS Research Summary, May 1998.
3. Saltzman, – The Low Glycemic Index Diet: Not Yet Ready for Prime Time- (comment), Nutrition Reviews 57(9):1999; Morris and Zemel, – Glycemic Index, Cardiovascular Disease, and Obesity,- same journal, same issue.
4. Lee, Klopp, Weindruch, Prolla, – Gene Expression Profile of Aging, and Its Retardation by Caloric Restriction,- Science 285(5432), 1999.
5. Quoted from an interview with Weindruch and Prolla in the November 1999 Life Extension (publication of the Life Extension Foundation, 1-800-841-LIFE).
6. Bubendorf et al., – Hormone Therapy Failure in Human Prostate Cancer: Analysis by Complementary DNA and Tissue Microarrays,- J. Natl. Cancer Inst. 91(20):1758-1764 (1999).
7. See, for example, Chen et al., – DNA Hypomethylation Leads to Elevated Mutation Rates,- Nature 395:89-93 (1998).
8. Migliaccio et al., – The p66^shc Adaptor Protein Controls Oxidative Stress Response and Life Span in Mammals,- Nature 402:309-313 (1999).

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LOOKING AHEAD – A FEW HIGHLIGHTS

What specific events might be coming up in the near future? We consulted our crystal ball, which revealed to us a few examples . . . .

In 2004, a Nobel Prize-winning physiologist writes a best-selling book called What It Means to Be Human, which concludes that being human means, in the 21st century, being able to choose for yourself what it means to be human.

The Nobel Prize for Physiology or Medicine and the Nobel Peace Prize for 2008 are won by the same scientists, who discover the genes that control irrational violent behavior and the signal-transduction pathways that regulate them. This knowledge, plus discoveries on the genetic and biochemical bases of the pygmy chimpanzees’ use of sex as a remedy for interpersonal conflict, leads to a new drug called “Make Love Not War” (a true aphrodisiac, not just a performance enhancer) that creates an immense controversy as its use results in a tremendous decline in the interest of young people in war and politics and creates a huge illicit subculture.

In 2012, the first person to run a three-minute mile loses his or her Olympic gold medal when post-race DNA tests reveal that he/she has racehorse mitochondrial DNA.

By 2048, The Sharper Image is selling universe lamps, which are small globes each containing a real universe of some 100,000,000,000 galaxies, each of which contains about 100,000,000,000 stars. Each universe lamp has an estimated lifetime of at least one trillion years. With no on-off switch (since they are always on), each lamp comes with a decorative cover so it won’t keep you awake at night. The universe lamp is guaranteed by The Sharper Image to contain at least one friendly, intelligent, humanoid species. For an additional charge of only 10 grams of gold, you get a miniature radio telescope and a CD-ROM that teaches you First Contact Protocol. Great for kids from 9 to 290!

Oh dear, the crystal ball has dimmed (or maybe it is just asking for another payment). Its final message as it fades out is: “Reality is likely to be a lot more amazing. . . .”

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A BIOMAKER FOR MORTALITY YOU CAN EASILY AND CHEAPLY MEASURE

You don’t have to be visibly falling apart and about to keel over to have an increased risk of death. So it’s nice to have some biomarkers you can easily detect to sound an alarm if your risk is increased. One such useful marker has been reported in a recent paper:¹ a slow return of heart rate to normal after exercise can predict an increased risk of mortality.

The authors note that the increase in heart rate that accompanies exercise is due in part to a reduction in the tone of the vagus nerve and that recovery of heart rate to normal immediately after exercise is a function of vagal reactivation. A generalized decrease in vagal activity is reported to be a known risk factor for death; hence, the authors hypothesized that a delayed fall in heart rate after exercise might point to a higher risk of mortality.

The researchers tested their hypothesis by measuring the recovery of heart rate after exercise, which was defined as the decrease in heart rate from peak exercise to one minute after the cessation of exercise. (After reaching peak workload, all patients spent at least two minutes in a cool-down period during treadmill testing at a speed of 2.4 km (1.5 mi) per hour at a grade of 2.5%.) The authors defined an abnormally slow recovery as a reduction of 12 beats per minute or less from the heart rate at peak exercise. They followed for six years 2,428 consecutive adults they saw at the Cleveland Clinic Foundation who had no history of heart failure, coronary revascularization, or heart pacemakers. The subjects had a mean age of 57 + 12 years, with 63% men.

They found that 26% of the patients had abnormally low values for heart-rate recovery. Over the six years, 213 deaths from all causes occurred. Of those who died, the majority (56%) had an abnormally low value. A low value for recovery of heart rate was strongly predictive of death, with a relative risk, after adjusting for various factors, of 2.0, which was independent of workload, the presence or absence of heart perfusion defects (as measured at the start of the study by thallium scintigraphy), and changes in heart rate during exercise. Not surprisingly, there was a strong association between a decreasing exercise capacity and an abnormal value for heart-rate recovery in both men and women.

All you need to keep track of your heart recovery rate is a heart-rate sports watch or similar device that you can buy for $30 and up, depending upon how fancy you want it.

References

1. Cole et al, “Heart-Rate Recovery Immediately After Exercise As a Predictor of Mortality,” New Engl. J. Med. 341(18):1351-1357 (1999).

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FOLIC ACID MAY REDUCE THE RISK OF CERTAIN CANCERS

Just as the FDA has resigned itself to having to allow a folic acid claim for the reduction of the risk of neural-tube-defect births (or, more precisely, has picked itself up after having been dragged kicking and screaming by both public and Congressional pressure to its new position), it had better get ready for the next folic acid claim: that folic acid may reduce the risk of some cancers.

A recent review¹ describes some evidence that folic acid may be protective for people at risk of developing colorectal, pancreatic, and breast cancer, especially for male smokers at risk for pancreatic cancer and for women regularly consuming moderate amounts of alcohol at risk for breast cancer. Folic acid is a key component in DNA replication and repair and DNA methylation, which are plausible mechanisms to account for its cancer-protective effects.

The greatest amount of evidence relating folate to cancer risk is in the case of colorectal cancer. The majority of the 20 published epidemiologic studies indicate that dietary folate intake is inversely associated with the risk of developing colorectal neoplasms in a dose-dependent fashion, reports the review. Very convincing evidence came from a prospective study involving 88,756 female nurses in the U.S. (the Nurses Health Study), which reported a 75% reduction in colorectal cancer risk in women using multivitamin supplements containing 400 mcg or more of folic acid for 15 years or more, compared with those not taking folic acid, after correcting for known confounding factors such as vitamins A, C, D, and E, and calcium. Animal studies and small, human, randomized intervention studies also support the protective effect of folate supplementation against colorectal cancer.

Women consuming at least 15 grams a day of alcohol were reported (using data from the Nurses Health Study) to have a 24% increased risk of breast cancer, compared to women consuming no alcohol. Alcohol has an adverse effect on folate transport and metabolism, so the study authors looked at the association between total folate intake and breast-cancer risk by levels of alcohol consumption. Among women consuming at least 15 grams a day of alcohol, there was a significant dose-dependent inverse association between total folate intake and breast-cancer risk. In this cohort, it was reported that total folate intake of at least 600 mcg per day was associated with a 45% reduction in breast-cancer risk, compared with 150-299 mcg per day. The protective effect of folate on breast-cancer risk was not evident for women consuming less than 15 grams a day of alcohol.

A case-control study conducted as part of the ATBC (Alpha-Tocopherol Beta-Carotene) Cancer Prevention Study, looking at 29,133 Finnish men over 7-10 years, reported that serum folate concentrations were inversely related to the risk of pancreatic cancer. Baseline serum levels in the highest percentile (over 4.45 ng/ml were associated with a 55% reduction in risk, compared to those at the lowest level of 3.33 ng/ml or less. (A similar inverse dose-response relationship was reported for vitamin B6.) This is especially good news, since pancreatic cancer is rapidly deadly, with current approved treatments not very effective.

References

1. Young-In Kim, “Folate and Cancer Prevention: A New Medical Application of Folate Beyond Hyperhomocysteinemia and Neural Tube Defects,” Nutrition Reviews 57(10):314-321 (1999).

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LOOKING AT YOUR HEAD – HAIR, HAIR, EVERYWHERE

A new report in Nature¹ tells an incredible story, that hair follicles are an immune-privileged site and can, therefore, be induced to grow in an incompatible host. In fact, in the study, hair follicles from one author (male) were implanted into a genetically unrelated and immunologically incompatible female recipient, another of the authors. All the implant sites healed rapidly and lacked any overt inflammatory reaction; each site of dermal-sheath implantation produced new follicles and fibers 3 to 5 weeks after the graft. The follicles were taken from the head and implanted onto the inner forearm; the resulting hairs from the implants were not fine, unpigmented vellus hairs that grow from the inner arm, but were larger and thicker, mostly pigmented, and were said to grow in variable directions. The authors propose that this might be a new treatment for hair loss.

It might indeed. But it might also lead to very entertaining (or, to some, appalling) new hair “styles.” Young people, rather than dying their hair, might have selected implants to give them multicolored heads of hair. Even beyond that, if hair follicles are indeed immune-privileged sites, then even interspecies hair transplants might be possible and desired by the more adventurous. Imagine a head of silky mink fur! Or how about an entire “coat” of mink fur?

References

1. Reynolds et al., “Trans-Gender Induction of Hair Follicles,” Nature 402:33-34 (1999).

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IS CONJUGATED LINOLEIC ACID AN ANTIOXIDANT?

There is a lot of interest in conjugated linoleic acid (CLA) because of its reported array of potentially beneficial effects, which include protective effects against atherosclerosis and carcinogenesis, changes in fat partitioning (body composition; specifically, increases in lean body mass and decreases in body fat), as well as increasing bone mass and normalizing diabetes in experimental animal models. In biological systems, CLA is incorporated into phospholipids, which are the major structural components of cell membranes.

The anticancer effects of CLA can be dramatic. For instance, in one study using severely combined immunodeficient mice, feeding 1% CLA in the diet inhibited local tumor growth of human breast adenocarcinoma cells inoculated subcutaneously, and it completely prevented the spread of breast cancer cells to lungs, peripheral blood vessels, and bone marrow, in contrast to controls.

At first, the effects of CLA were hypothesized to be the result, at least in part, of CLA’s being an antioxidant, but it may be that CLA is a pro-oxidant, at least as reported in two prior papers^1,2 and a new paper.³ The new paper reports that CLA-containing phospholipids increased oxygen consumption with increasing concentration up to 5 mol%, which is the concentration that had been previously shown to result in the greatest beneficial effects on mammary-cancer prevention in lab animals. CLA-containing phospholipids in cell membranes also increased the oxygen permeability. The authors located the enhanced oxygen-diffusion-concentration product in the region of the CLA conjugated double bonds in the membranes and suggest that “[t]he combined effects of perturbing membrane structure and increasing oxygen diffusion-concentration products by double-bond conjugation imply that CLA molecules probably increase the biomolecular collision frequency of oxygen, and/or reactive oxygen species, with target molecules, thereby accelerating the oxygen consumption.” They add that they do not know whether this effect contributes to the observed beneficial effects or anticancer effects of CLA.

We suspect that the chemical actions of CLA serve as a specific signal that induces upregulation of antioxidant protective mechanisms and that this may account for its anticancer and antiatherosclerosis effects. It has been established that oxidants and their scavenging by antioxidants may selectively regulate certain signal-transduction pathways, the study of which is a new cutting edge in basic biomedical research.⁴ CLA may be a regulator of gene expression. We look forward to more research on this intriguing possibility.

References

1. van den Berg et al., “Reinvestigation of the Antioxidant Properties of Conjugated Linoleic Acid,” Lipids 30:599-605 (1995).
2. Chen et al., “Reassessment of the Antioxidant Properties of Conjugated Linoleic Acid,” J. Am. Oil Chem. Soc. 73:749-753 (1997).
3. Yin et al., “Effects of Conjugated Linoleic Acid on Oxygen Diffusion-Concentration Product and Depletion in Membranes by Using Electron Spin-Label Oximetry,” Lipids 34(10):1017-1023 (1999).
4. A new journal in this field is Antioxidants & Redox Signaling, published by Mary Ann Liebert, Inc., 2 Madison Ave., Larchmont, NY 10538-1962, (914)834-3100.

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MORE EVIDENCE LINKS GREEN TEA TO REDUCED RISK OF SOME CANCERS

A group of researchers has reported in a letter to Nature Medicine¹ that the main flavonol of green tea, epigallocatechin-3-gallate (EGCG), at concentrations equivalent to that in the plasma of humans drinking moderate amounts of green tea (two or three cups a day is adequate), is effective (as determined by cell culture and chemical analytic methods) in reducing tumor-cell invasion by 50%.

EGCG had already been reported to inhibit urokinase, an enzyme implicated in tumor invasion. The new data indicate that EGCG inhibits tumor-cell invasion and directly suppresses the activity of two proteases (MMP-2 and MMP-9) that are among the most frequently overexpressed in cancer and angiogenesis.

The authors suggest that EGCG, in combination with angiostatin (an inhibitor of angiogenesis), might be an effective clinical treatment for cancer.

References

1. Garbisa et al., “Tumor Invasion: Molecular Shears Blunted by Green Tea,” Nature Medicine 5(11):1216 (1999).