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.
- 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).
- 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.
- "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.
- 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.
- 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).
- 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.
- 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.
- 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