The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 4 No. 5 • September 2001

NONE DARE CALL IT TREASON?

I hope your committee will not permit doubts as to constitutionality, however reasonable, to block the suggested legislation.

- F. D. Roosevelt: Letter to the Ways and Means Committee of the House of Representatives (on the Guffey-Snyder Coal Bill, July 1935)

The United States Constitution has proved itself the most marvelously elastic compilation of rules of government ever written.

- F. D. Roosevelt: Radio speech, March 2, 1930

Our Constitution is so simple and practical that it is possible always to meet extraordinary needs by changes in emphasis and arrangement without loss of essential form.

- F. D. Roosevelt: Inaugural address, March 4, 1933


FDA UPDATE: THE LATEST NEWS!
We are cautiously optimistic to learn that First Amendment attorney Daniel F. Troy, a former colleague of Jonathan Emord when he was working at the law firm Wiley, Rein & Fielding, has been named by Health & Human Services Secretary Tommy Thompson to the position of FDA chief counsel. This surprising turn of events has no doubt occurred because of our victory in the court of appeals for the D.C. circuit in Pearson v. Shalala (Jan. 15, 1999); the unwillingness of the FDA to comply with that court decision, as well as other First Amendment decisions at the D.C. district court that followed in support of the circuit court decision; and the expenses that have resulted to the FDA. Our perseverance in hounding the FDA with First Amendment suits resulted in the FDA's admitting that it was spending more of its regulatory money trying to deal with Pearson v. Shalala (i.e., trying to avoid complying with it) than on any other regulatory matter! Apparently, the Bush administration has now recognized that the FDA cannot continue dodging its First Amendment responsibilities. Hence, the appointment of a First Amendment attorney as its chief counsel.

According to Jonathan Emord, Mr. Troy and he had frequent discussions about First Amendment issues at Wiley, Rein & Fielding, and Emord says that "[Troy] strongly opposes government censorship (perhaps as strongly as I do)." Troy, in fact, was one of the attorneys at Wiley, Rein & Fielding who sued the FDA on First Amendment grounds in a similar case, Washington Legal Foundation v. Henney, that involved the FDA's restrictions on communication of off-label uses of prescription drugs. (That case was ruled by the court to be moot, unfortunately, after the FDA claimed it had no intention of taking adverse enforcement action.) Emord notes that "The decision is . . . extraordinary because it removes a principal obstacle to FDA compliance with the First Amendment, namely, former FDA Chief Counsel Margaret Jane Porter." (Porter has, Emord says, been reassigned to work at the Senior Executive Service Federal Executive Institute in Charlottesville, Virginia.)

We have also been informed by Emord that another Wiley, Rein & Fielding alumnus, Alex Azar, has been confirmed (August 3) as the Health & Human Services general counsel. Although Emord does not know Mr. Azar personally, he believes that Mr. Azar too is an advocate of the First Amendment and, hence, will be more favorable to our cause.

Wow! The money that has been spent on our First Amendment assault against the FDA has certainly been money well spent. We still have numerous health claims pending. (This is an excellent time to press forward for more FDA reforms, so please do not think this is the end of our efforts. Please do continue to send in your donations to the Pearson & Shaw Litigation Fund, c/o Emord & Associates, 5282 Lyngate Court, Burke, VA 22015. See www.emord.com. Thank you very much!)


CAN PANCAKES SAVE YOUR LIFE?
Maybe, depending upon what you put in them. In our next battle with the FDA, we will be making a health claim for our delicious fish-oil (DHA and EPA), B12, B6, folic acid, and vitamins C and E-fortified pancake mix. The FDA alleges that the court of appeals decision in Pearson v. Shalala applies only to dietary supplements, not to foods. In other words, the FDA claims that the First Amendment doesn't protect speech about food! We plan to blow that idiocy out of the water and win First Amendment protection for truthful health information about foods with a lawsuit based upon our product if the FDA decides not to permit a health claim that our pancake mix "may reduce the risk of cardiovascular disease." (The claim is based upon the DHA, which reduces the risk of sudden cardiac death from arrhythmia, and the folic acid, B12, and B6, which reduce homocysteine levels. The E and C are in there to replace that used by the body to protect highly polyunsaturated fatty acids such as DHA and EPA.) Each serving of our pancakes contains as much DHA as a 100-gram serving of Chinook or pink salmon. Of course, if the FDA allows the claim, then we have won without having to resort to another lawsuit.

Note: Because the FDA has not classified vitamins B6, C, and E as GRAS (!), we will be able to put only very small amounts in the pancake mix. This is just another outrageous example of the FDA's bias against dietary supplements.


DRUG REIMPORTATION: HHS AND FDA SAY NO, CONGRESS MAY SAY YES (AGAIN)
As we reported in our July newsletter, HHS Secretary Tommy Thompson and the FDA are opposed to allowing Americans to reimport FDA-approved drugs manufactured in FDA-approved factories in this or other countries. The reason they give is that the reimported drug might be counterfeit or adulterated, and FDA can't guarantee safety and efficacy. A bill containing a reimportation provision actually passed Congress last year, but Clinton refused to implement it, supposedly for these health reasons.

Now, however, an amendment to an agricultural spending bill that would allow such reimportation (sponsored by Gil Gutknecht, R-Minn.) has been approved in the House, 324-101. The provision would allow Americans to buy up to a 60-day supply of drugs for personal use, not for resale. There is a battle brewing in the Senate over the issue, and passage is questionable. Everything depends on which special interest (folks who want to import drugs vs. pharmaceutical companies) is noisiest and spends the most money. As anyone knows who studies political power struggles, the advantage almost always goes to the small group that gets very large, concentrated benefits as opposed to a large group with small, diffuse benefits.

- Chemical Marketing Reporter, July 16, 2001


THE SCIENCE OF GLOBAL WARMING
Richard S. Lindzen, a professor of meteorology at MIT, was one of eleven members of the National Academy of Sciences panel on climate change. As a result of what he considered misrepresentation by the media of the resulting report by that NAS panel, Dr. Lindzen published an analysis/opinion piece that appeared in a number of publications, including The Wall Street Journal, June 11, 2001. Sad to say, his critical remarks were nowhere noted in the scientific press (at least in the 50 or so journals to which we subscribe, including Nature and Science), which continued to report on the NAS panel as if there were a consensus and that that consensus was in support of the Kyoto Treaty. Dr. Lindzen says otherwise.

According to Dr. Lindzen, CNN's Michelle Mitchell was "typical of the coverage when she declared that the [NAS] report represented a 'unanimous decision that global warming is real, is getting worse, and is due to man. There is no wiggle room.'" Lindzen's response: "As one of 11 scientists who prepared the report, I can state that this is simply untrue." For example, he notes that far too much public attention has been paid to the "hastily" prepared summary than to the body of the report. "Our primary conclusion was that despite some knowledge and agreement, the science is by no means settled. We are quite confident (1) that global mean temperature is about 0.5 degree Celsius higher than it was a century ago; (2) that atmospheric levels of carbon dioxide have risen over the past two centuries; and (3) that carbon dioxide is a greenhouse gas whose increase is likely to warm the earth (one of many, the most important being water vapor and clouds). But - and I cannot stress this enough - we are not in a position to confidently attribute past climate change to carbon dioxide or to forecast what the climate will be in the future. That is to say, contrary to media impressions, agreement with the three basic statements tells us almost nothing relevant to policy discussions."

Dr. Lindzen noted that the NAS panel was asked to evaluate the work of the United Nations Intergovernmental Panel on Climate Change, focusing on the Summary for Policymakers, the only part ever read or quoted. He concludes that "Within the confines of professional courtesy, the NAS panel essentially concluded that the IPCC's Summary for Policymakers does not provide suitable guidance for the U.S. government." He feels that "Science, in the public arena, is commonly used as a source of authority with which to bludgeon political opponents and propagandize uninformed citizens. This is what has been done with both the reports of the IPCC and the NAS."

You owe it to yourself, if you want to be fully informed on global warming, to read Dr. Lindzen's whole analysis.


MARGIN OF ERROR IN THE IPCC REPORT: IS GLOBAL WARMING STATISTICALLY SIGNIFICANT?
Biomedical scientists generally use a 99% or 95% confidence interval when they talk of something being statistically significant. According to Dr. Richard S. Lindzen (see above), the margin of error used in the IPCC report is much smaller, a 60% confidence level. This means that, assuming that the numbers they are using are correct (questionable, considering the large uncertainties), there is still a 40% likelihood that the results are due to chance. And for this, we are supposed to give up our freedom to engage in nearly all economic activities to a committee of government elites who will approve or disapprove our every action at tremendous expense to us?

- Environment & Climate News, June 2001, pp. 4-5


DEMOGRAPHICS AND ECONOMICS OF GLOBAL WARMING
According to figures shown in the July 2001 American Demographics, a December 2000 poll conducted by Zogby International on global warming found the following (among other things): When asked whether (A) "The U.S. should support the Kyoto Protocol, which requires American businesses to have their industries conform to higher standards than industries in developing nations" or (B) "The U.S. should oppose the treaty because it places tough standards on U.S. industries with little or no restrictions on industries in developing nations that would cost American jobs and raise costs to consumers," 51% of females versus 40% of males supported A. This is consistent with voting records in recent elections, which show women much more likely to vote for big government than men. Also, when asked whether global warming was a very serious problem, a fairly serious problem, not a very serious problem, or not at all serious, 75% of those polled said it was very or fairly serious. But when asked whether they would be willing to pay an extra 25 cents per gallon of gas to reduce pollution and global warming, 48% said yes, while 49% said no. (The price increase required for Kyoto Treaty compliance would probably be between $1.00 and $1.50 per gallon.) This looks like so much of politics, where spending lots of money for a purported collective good is great, but only if somebody else has to pay for it.


THE HEREDITY OF HUMAN LONGEVITY
A very interesting paper1 has reported using a database of European royal and noble families 5779 adult daughters (30+ years) and their parents, all born 1800-1880, the correlation between the daughters' lifespan and the lifespan of mothers and fathers. (Daughters were chosen because they are far less likely than sons to die young from violent causes.) The results showed that, up to the age of 85, the daughters' lifespans had virtually no resemblance to those of their mothers, whereas for mothers who died at the age of 85 or older, the daughters had a very high degree of heritability. They found that for each additional 10 years of lifespan (beyond 85) for the longer-lived mothers, daughters gained an additional 4.12 ± 2.04 years of lifespan on the average. The authors sum up the relationship: "Thus, after maternal age of 85 years, the narrow-sense heritability of human lifespan increases from virtually zero to 82.4 ± 40.8% for mother-to-daughter familial transmission of lifespan. This indicates that maternal age of 85 years could be considered as a demarcation point for women's longevity (its lower boundary)."

Fathers had a similar effect on daughters' lifespan, except that the demarcation point is for fathers aged about 75 years. Daughters born to shorter-lived fathers (died before 75 years) do not inherit paternal lifespan. The authors found that "for each additional 10 years of lifespan of longer-lived fathers (died after 75 years), daughters gain additional 2.36 ± 0.78 years of lifespan on average. Thus, after paternal age of 75 years, the narrow-sense heritability of human lifespan (doubled regression slope coefficient) increases from virtually zero to 47.2 ± 15.6% for father-to-daughter familial transmission of lifespan."

Reference

  1. Gavrilova and Gavrilova, "When Does Human Longevity Start?: Demarcation of the Boundaries for Human Longevity," J Anti-Aging Medicine 4(2):115-124 (2001).


DOES MARIJUANA BOOST HEART ATTACK RISK?
A study (published in the June 12, 2001 Circulation) was reported in the July 14, 2001 Science News. Researchers at the Beth Israel Deaconess Medical Center and Harvard Medical School interviewed 3882 people a few days after they survived a heart attack. The researchers reported that 124 persons had said they smoked marijuana in the past year, nine within one hour of the attack. On the basis of these subjects, they estimated that the risk of having a heart attack rises fivefold during the hour after smoking pot.

Three of the nine people who'd had a heart attack within one hour of smoking marijuana admitted to having taken cocaine, having sex, or both. After these people were excluded, marijuana smoking within the hour still coincided with a tripled risk, according to the researchers.

Our Comments: Unless the use (or not) of cocaine is verified, what subjects say is not very reliable. For example, on the basis of hair analysis, the prevalence of cocaine use may be three to five times as high as that estimated by standard surveys and interviews of patients.1 It is well known that cocaine use increases the risk of cardiovascular events. For example, the risk of heart attack is increased 24-fold during the sixty minutes after the use of cocaine in persons who are otherwise at relatively low risk.1

The next problem is that the researchers interviewed only the subjects who survived a heart attack, but not those who died. Did the people who died have a disproportionately large percentage of individuals who didn't use marijuana? Without the data, we don't know.

Finally, while there are well-known mechanisms explaining why cocaine increases cardiovascular events, it is not clear why marijuana would do so.

Reference

  1. Lange, Hillis, "Cardiovascular Complications of Cocaine Use," N Engl J Med 345(5):351-358 (2001).


REGULATION OF GLUCOCORTICOIDS BY MELATONIN AND GROWTH HORMONE PROTECT T LYMPHOCYTES
Sustained release of stress hormones, glucocorticoids (GC), causes a number of deleterious effects, including damage to the brain cells that provide GC feedback regulation. There is an age-related decrease in the sensitivity of pituitary corticotropes to glucocorticoids in vitro as early as middle age in rats. Using the dexamethasone suppression test, it has been shown that this alteration in the HPA (hippocampus-pituitary-adrenal) axis with aging is due to an insufficient inhibition of basal production of endogenous glucocorticoids by dexamethasone, via inhibition of CRH (corticotropin-releasing hormone) and ACTH (adrenocorticotropic hormone) secretion in the hypothalamus and pituitary, respectively.1

Glucocorticoids can damage the hippocampus, an important brain area for memory (among other things). Insults whose toxicity in the rodent hippocampus are exacerbated by GCs include exposure to excitotoxins, hypoxia-ischemia, hypoglycemia, an electron transport uncoupler, cyanide, the beta-amyloid peptide, HIV-infected monocytes, and others.2 Sustained major depression is associated with elevated GC concentrations in about half of patients.2 Studies have shown hippocampal-dependent memory problems in Cushing's disease, where the extent of GC hypersecretion predicts the extent of memory impairment.2

Glucocorticoids can increase oxidative stress. One study (Beaver and Waring) reported that glutathione concentrations decrease after dexamethasone administration, while another (Behl et al.) has shown that GCs enhance oxidative stress-induced cell death in neurons.3 One mechanism for this is that GCs decrease glutathione peroxidase and increase superoxide dismutase.3 The rise in SOD would increase intracellular levels of hydrogen peroxide, while the decreased glutathione peroxidase would not allow the conversion of the hydrogen peroxide into nontoxic products.

Glucocorticoids in the high physiological range readily induce apoptosis in nonselected thymocytes in the thymic cortex, thus impairing immune function. In fact, it is thought that GC may be responsible for age-related thymic involution; this is supported by the finding of a rise in thymus weight by adrenalectomy in mice.3 Induction of T lymphocyte apoptosis is why GCs are used to treat certain autoimmune disorders. Melatonin has been found to downregulate the mRNA for the GC receptor in thymocytes, thus protecting them from GC-induced apoptosis.3 Moreover, recombinant human GH partially alleviated the GC-induced suppression of DNA synthesis in human peripheral T lymphocytes.4

References

  1. Revskoy, Redei, "Decreased in Vitro Sensitivity to Dexamethasone in Corticotropes from Middle-Age Rats," Exp Gerontol 35:237-242 (2000).
  2. Sapolsky, "Mini-Review: Glucocorticoids, Stress, and Their Adverse Neurological Effects: Relevance to Aging," Exp Gerontol 34:721-732 (1999).
  3. Sainz et al., "Melatonin Regulates Glucocorticoid Receptor: An Answer to Its Antiapoptotic Action in Thymus," FASEB J 13:1547-1556 (1999).
  4. FASEB J (June 27, 2001) 10.1096/fj.00-0702fje.


SPONTANEOUS REGRESSION OF MELANOMA
One would have thought that there would be a low frequency of spontaneous complete regression of melanoma. However, that appears not to be the case. Although there are no hard statistics available, Ross Barnetson, M.D., of the Royal Prince Alfred Hospital at the University of Sydney, Australia, estimates that the rate is between 10% and 20%, based on histological studies that show that 25% of melanomas have evidence of partial regression. The Australian group's studies have shown that activated CD4+ T lymphocytes are important in the induction of regression and that Th1 cytokines are involved. They observed an increased number of CD4+ T lymphocytes in regressing tumors only within the regressing lesions themselves, not in surrounding tissues. Further, Barnetson and his colleagues have studied regression in basal cell carcinomas of the skin, where there is said to be evidence of regression in as many as 50% of tumors.

- Printz, "News: Spontaneous Regression of Melanoma May Offer Insight into Cancer Immunology,"
J Nat Cancer Inst 93(14):1047-1048 (2001)


MORE ON CHOLESTEROL AND STATINS: POSSIBLE EFFECT OF STATINS ON CANCER RISK?
We mentioned in our July 2001 issue reasons why we considered the discussion by the National Cholesterol Education Program of the options for individuals who want to reduce their cholesterol levels to be inadequate. With the new lower cholesterol goals they've set and their recommendations for the use of statins, the number of Americans taking these prescription drugs could triple from the current 13,000,000. As David Kritchevsky, a researcher at the Wistar Institute in Philadelphia, Pennsylvania, put it: "I wish I was as sure as they are that putting a bunch of relatively healthy people on these drugs, probably for life, is good for them, and safe. Statins are very powerful, very effective drugs for lowering cholesterol levels, but they can also cause liver damage and muscle weakness. They're not totally benign. I also wonder if anyone has given thought to how low we want to go. A conference of all the cholesterol-lowering honchos, published in Circulation in 1992, showed that mortality at cholesterol levels below 160 mg/dL was the same as mortality at levels above 260 mg/dL."1

Two new papers published in the August 2001 The Journal of Clinical Investigation2,3 have reported that statins (inhibitors of HMG-CoA reductase, an enzyme that is part of the cholesterol-manufacturing pathway) also promote the sprouting of new blood vessels from differentiated endothelial cell progenitors. In fact, the statins did so as well as VEGF (vascular endothelial growth factor). This may, of course, explain some of the beneficial effects of statins in cardiovascular disease. However, the sprouting of new blood vessels in cancer (angiogenesis) is very undesirable, and one can't help but wonder whether statins may increase the risk of some cancers. It is certainly something one would want to find out about before recommending statins for many millions more people who are healthy except for higher-than-optimal cholesterol levels.

References

  1. "Health & Nutrition News," Inform, August 2001.
  2. Dimmeler et al., "HMG-CoA Reductase Inhibitors (Statins) Increase Endothelial Progenitor Cells Via the PI 3-Kinase/Akt Pathway," J Clin Invest 108(3):391-397 (2001).
  3. Llevadot et al., "HMG-CoA Reductase Inhibitor Mobilizes Bone Marrow-Derived Endothelial Progenitor Cells," J Clin Invest 108(3):399-405 (2001).


PREVENTION OF FAT-INDUCED INSULIN RESISTANCE BY SALICYLATE
We've been experimenting with salicylate supplements for years as "preconditioning" to increase the production of heat-shock proteins, known to decline with aging.1 A new paper2 reports another possible reason to use salicylate supplements, to prevent insulin resistance resulting from elevation in plasma fatty acids. This is very exciting, because insulin resistance, as in type 2 diabetes, is a major contributor to aging.

Nearly 100 years ago, Williams et al. (referenced in paper 2 below) noticed that high-dose salicylate treatment reduced glucose in the urine of diabetes patients. Then, in 1957, Reid and colleagues showed that 10-14 days of aspirin treatment improved the results of oral glucose tolerance tests in diabetics. Aspirin, acetylsalicylic acid, is partially broken down into salicylic acid in the stomach, the remainder being broken down during circulation. That it took so long to test salicylate's effects on the insulin-signaling pathway was probably due to two factors: many of the details of insulin signaling have been discovered recently, and salicylic acid is a natural substance that cannot be patented. The new study we report here was funded by tax money from the United States Public Health Service.

It was discovered recently by Yin and colleagues that salicylate inhibits the activity of IkB kinase-beta (IKK-beta), a serine kinase. The authors of the new paper2 hypothesized that salicylate might prevent fat-induced insulin resistance in skeletal muscle by inhibiting the activity of IKK-beta and subsequent serine phosphorylation of IRS-1 (insulin receptor substrate-1) by IKK-beta and decreased activiation of IRS-1- associated PI 3-kinase. They tested their hypothesis by examining whether high-dose salicylate pretreatment would prevent fat-induced alterations in insulin activation of IRS-1 associated PI 3-kinase and skeletal muscle glucose uptake in rats. In addition, they examined mice with the IKK-beta gene knocked out to see whether these mice are protected (compared to non-KO mice) against fat-induced alterations in skeletal muscle signaling and action.

There was a long, detailed description of the results, which is well worth reading. Some of the results included the following: Insulin-stimulated whole body glucose uptake was decreased by 37%, with skeletal muscle glucose uptake decreased by 41%, with the lipid infusion. Salicylate pretreatment prevented both these effects. Salicylate pretreatment also prevented the most profound change, a 66% decrease in insulin-stimulated skeletal muscle glycogen synthesis with lipid infusion. Insulin-stimulated IRS-1-associated PI 3-kinase activity in skeletal muscle was decreased by 38% with lipid infusion, while this effect was prevented by salicylate pretreatment.

The IKK-beta knockout (KO) mice were protected against fat-induced insulin resistance in skeletal muscle. For example, lipid infusion did not alter insulin-stimulated whole body and skeletal muscle glucose uptake in the IKK-beta KO mice compared with the controls.

The researchers' findings indicate that the defect in insulin signaling with lipid infusion is responsible for the defects in glucose metabolism. Thus, the mechanism by which salicylate prevents insulin resistance may involve inhibition of IKK-beta. Interestingly, the paper reports that tumor necrosis factor-alpha (TNF-alpha), a well known proinflammatory cytokine that is released by adipocytes (fat cells), activates NF-kB, a transcription factor involved in immune, inflammatory, and apoptotic responses, by stimulating IKK activity; and salicylate has been demonstrated to inhibit TNF-alpha-induced stimulation of IKK activity. TNF-alpha has been shown to promote insulin resistance in adipocytes and skeletal muscle by decreasing insulin activation of IRS-1 tyrosine phosphorylation and IRS-1-associated PI 3-kinase.

Salicylate Treatment
The pretreatment of the rats with salicylate involved starting at 1200 hours on the day before the experiment, with 42 mg/kg of salicylate fed using oral gavage at 6-hour intervals. In scaling a human dose from a rat dose, you don't want to scale on the basis of body weight, which would give you a massive overdose for the human. A more rational way is to scale on the basis of body surface area or the amount of food eaten. The rats used in this study were male Wistar rats that weighed 275-300 grams, each of which would probably eat about 20 grams of food per day. On that basis, roughly 1 gram per day of salicylate for a human is about what the rats were getting as salicylate pretreatment, when scaled up to a human dose on the basis of food eaten. You can get salicylate from Doan's Extra Strength magnesium salicylate tablets, each of which contains 429.82 mg of salicylate. The recommended dose for minor backache pain is two tablets every six hours, not to exceed eight tablets a day, for up to ten days.

Be sure to read all the warnings on the label before use. Take them seriously. Taking salicylate is not like taking vitamin E. People with impaired kidney function should not be taking salicylate, unless recommended by their doctor. A high-pitched ringing in your ears means you are taking too much. If this happens, you should discontinue use for a few days until the ringing goes away

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