The Durk Pearson & Sandy Shaw®
Life Extension News™
"I have yet to see any problem, however complicated, which, when you looked at it in the right way, did not become still more complicated."
— Poul Anderson, in New Scientist, Sept. 25, 1969
"At this time, three fruits—oranges, apples, and bananas—account for 50% of all fruit servings. Iceberg lettuce, frozen potatoes, and potato chips account for 33% of vegetable servings. Diets composed of lean meats, fish, fresh vegetables, and fruit are likely to cost more."
— Adam Drewnowski, Director, Nutrition Science Program, University of Washington; reported in Food Technology, June 2004
"… the Continuing Survey of Food Intake by Individuals data indicate that people with high incomes are more likely to choose diet soda and skim milk, whereas people with low incomes tend to choose regular soda and whole milk. Thus obesity may be related more to education and choice rather than [to] economics."
— Richard Mattes, Professor, Dept. of Foods & Nutrition, Purdue University; reported in Food Technology, June 2004
Comment: The amount and type of education you buy, in addition to other purchase choices you make (including those concerning what foods to buy), are all influenced by cost. Going by the prices in our local supermarket, a diet heavy in a variety of fresh fruits and vegetables is much more expensive than a diet low in those foods. Moreover, the prevention by the FDA of food companies’ dissemination of truthful, nonmisleading information concerning specific benefits of eating these expensive foods has a negative impact on the likelihood of the less informed public’s choosing to buy them. We and our coplaintiffs continue with the expensive court battles to force the FDA to obey the First Amendment’s mandate that the Congress (and, by delegation, the FDA) “make no law … abridging the freedom of speech, or of the press.” One of our suits, Whitaker v. Thompson, is now before the U.S. Supreme Court in a petition for cert. This is an important case because the FDA claims that nobody can put truthful information concerning the effect of a dietary supplement on a current disease (treatment claim) on a label or in labeling (literature that accompanies a product) of dietary supplements, because this would turn the supplement into an unapproved drug. We argue that the First Amendment prohibits the FDA from preventing the communication of truthful, nonmisleading information and that it also prohibits the severity of regulations (as in drug vs. dietary supplement) being based solely upon the content of truthful speech.
On May 27, 2003, the White House urged government health agencies to encourage Americans to increase their consumption of foods rich in omega-3 fatty acids …Comment: The FDA has actually stated, in response to the White House statement, that getting the public to consume more foods rich in omega-3 fatty acids is one of the FDA’s goals. So why is it that the only health claim the FDA allows (after seven years of litigation) for omega-3 fatty acids found in fish oils is the following “qualified” claim: “Consumption of omega-3 fatty acids may reduce the risk of coronary heart disease. FDA evaluated the data and determined that, although there is scientific evidence supporting the claim, the evidence is not conclusive.” We have argued (though not yet in an FDA lawsuit) that this FDA disclaimer actually discourages people who rely upon this information from consuming omega-3 fatty acids because it makes the benefits of omega-3 fatty acids appear much weaker than they are, as reported in hundreds of papers in the scientific literature. In order to prove that their disclaimer is discouraging, rather than encouraging, consumption of omega-3 fatty acids (which, if proven, would be a powerful weapon to use in a suit against the FDA’s misleading “disclaimer”), we would need to commission a professionally conducted public survey. The cost of such a survey has been ascertained; it would run about $65,000. Unfortunately, none of the remaining coplaintiffs, including ourselves, have the money to spare to pay for this survey. About 150,000 Americans continue to die each year from preventable sudden-death heart attacks.
Table of Contents This Issue
Do Food Ads Promote Childhood Obesity? Two Studies Suggest They Don’t
Two new studies have examined the effect of food ads on children and teenagers. One, supported by the Association of National Advertisers and the Grocery Manufacturers of America, found that children under 12 see fewer food and fast food ads today than a decade ago.1 The other, which came from the Federal Trade Commission’s Office of Policy Planning,1 found that the percentage of eighth, tenth, and twelfth graders who watch four or more hours of TV a day on weekdays has been dropping since 1991. Todd J. Zywicki, a law professor at George Mason University, who conducted the study, states that kids are spending more time playing video games and watching more videos. “They may have more screen time, but they see less [sic] ads,” he said. He considers the case for increased food-ad exposure as a cause for obesity to be pretty weak. He also notes that kids are watching more cable as compared to noncable TV, and that 72% of broadcast TV spots were for food, compared to 36% of cable spots.
The first study reported that kids today are seeing fewer food and fast food ads than a decade ago. They found that in 1994, kids under 12 saw an average of 5909 broadcast and cable TV ads for food or fast food, while in 2003, they saw 5038.
One would hope that any consideration of government regulation of truthful ads would be moot, in light of the First Amendment and of recent commercial speech decisions by the courts, but the fear of well-funded lawsuits against food companies is certainly realistic, hence the need for data rather than conjectures about what is behind increasing obesity among children.
- Teinowitz. Don’t blame ads: kids view fewer food commercials. Advertising Age, June 14, 2004.
Good News for Medical Marijuana Patients and Constitutional Strict Constructionists
The Ninth Circuit Court of Appeals has ruled that the federal government does not have the constitutional authority to regulate or prohibit medical marijuana activities that are purely intrastate in nature.1 The ruling by a three-judge panel was based upon the limits of the Commerce Clause and the Fifth, Ninth, and Tenth Amendments, as well as arguments that medical necessity is a valid defense for patients facing federal prosecution. The U.S. “Justice” Department, which lost the case, then appealed for an en banc (the entire court) hearing to reconsider the ruling, but was denied unanimously.
This is a very exciting federalism decision coming unexpectedly from the liberal Ninth Circuit, where we didn’t expect much sympathy for limits on federal government powers, no matter what the Constitution says. The Justice Department may, of course, appeal to the U.S. Supreme Court, where, for good or bad (if they accept the case), the Supremes will have to consider the constitutional limits of federal powers when they apply to an outcome they may not particularly care for. If they follow the precedent of U.S. v. Lopez and a few others, federalism may become a serious hindrance to federal prosecution of the war on drugs, at least as it applies to purely intrastate activities. In the meantime, medical marijuana users in states where medical marijuana is legal and which are included within the jurisdiction of the Ninth Circuit, including California, Nevada, Alaska, Hawaii, Oregon, and Washington, are protected from federal prosecution.
We ourselves filed a medical marijuana suit in 1997 (with Jonathan Emord as our attorney) against the federal government (Case No. 1:97CV00462) in the Federal District Court of the District of Columbia, based upon the limits of the Commerce Clause and the First, Ninth, and Tenth Amendments. We lost at the district court level with a stupid decision, but we did not have and could not raise the $60,000 that we needed to appeal to the court of appeals. Our brief was an excellent one, though, and we are happy to see that some of our arguments were used by the later case that won.
- Raich v. Ashcroft, Ninth Circuit Court of Appeals, December 2003.
Mechanism Discovered for Protective Effects of Cardiac Preconditioning
Preconditioning is the protective process that occurs when the heart is exposed to brief periods of reduced oxygen (ischemia). After such exposures, there is a brief (hours to a day or so) period during which the heart is resistant to additional exposures to ischemia and, hence, has reduced amounts of damage and cell death (as compared to nonpreconditioned hearts). Understanding how preconditioning works has been a longtime goal of researchers.
A new paper1 reports discovery of a mechanism that is not only of great theoretical interest but also potentially of great practical use, as there are methods available to make use of it. Many pathways have been found that are involved in preconditioning, but the new paper finds that these all converge on glycogen synthase kinase-3beta, an enzyme that is recognized as a central feature in many signaling systems.2 Lithium and other substances that inhibit glycogen synthase kinase-3beta (GSK-3beta) are cardioprotective. Low-dose lithium is one of the constituents of our new formulation for protecting cognitive abilities.
The authors found that one of the effects of reperfusion injury in the heart is a reduction in the reactive oxygen species threshold for induction of the mitochondrial permeability transition; the latter is an important part of mitochondrial death pathways. They found a number of agents that inhibit GSK-3beta and concluded that “… the general mechanism of protection is the convergence of these pathways via inhibition of GSK-3beta on the end effector, the permeability transition pore complex to limit MPT [mitochondrial permeability transition] induction.”
There were two classes of these cardio/neuroprotective agents: in one group, there was protection over a prolonged period of time (hours to a day or two), long after there was a significant amount of the substance in the bloodstream (the authors call this “memory”), while the other group provided protection while the substance was in the bloodstream but not afterward (these had no “memory”). All the substances enhanced the mitochondrial permeability transition reactive oxygen species threshold over control by about 35–50%. The memory group included diazoxide, Hoe, the peptide DADLE, and cyclosporine A, as well as bradykinin. The nonmemory group included receptor tyrosine kinase ligands (insulin and IGF-1), GLP-1, and others, as well as lithium.
The memory group of substances caused mitochondrial swelling by inducing free radicals. The authors found that preconditioning provided by the entire mitochondrial-sweller class (including hypoxic preconditioning) is prevented by reactive oxygen species scavengers. The memory effect thus appears to be due to the induction of free radical protective mechanisms, such as heat shock proteins, which is why you don’t get it if excess free radical scavengers are present. Lithium, a nonsweller, is one of the nonmemory preconditioners and does not depend upon the presence or absence of free radical scavengers.
The authors conclude, “Thus, it might be reasonable to consider adding Li+ (or another GSK-3 inhibitor) to GIK [glucose-insulin-potassium] in the treatment of acute ischemic syndromes, myocardial infarction, and stroke.” We note that, in our judgment a small inhibition of GSK-3beta will still provide worthwhile protection.
Lithium and inhibition of glycogen synthase kinase-3beta in cellular oxidative resistance
In another new study,3 researchers have found that, in clones of a particular type of cell (the mouse hippocampal neuronal cell line HT22) that is resistant to oxidative stress caused by glutamate* and hydrogen peroxide, the amount of inactivated glycogen synthase kinase-3 beta (GSK-3beta) is elevated compared to sensitive clones. They found that pharmacological inhibition of GSK-3beta by lithium in the parental neuronal cells (that are sensitive to oxidative stress) resulted in an increased tolerance to glutamate and hydrogen peroxide, “suggesting that GSK-3beta is involved in the control of oxidative stress resistance in these cells.”
*Glutamate excitotoxicity is thought to be part of the processes causing neurotoxic damage in Alzheimer’s and several other neurologic diseases.
The authors note, “These findings are interesting in the [sic] light of the well-established link between cell survival and GSK-3beta. While GSK-3beta activation is involved in apoptotic (programmed cell death) process, its inhibition is part of antiapoptotic signaling pathways like Wnt-signaling, the PI-3 kinase, and the MAP-kinase pathway.” Moreover, inhibition of GSK-3beta protects cortical and hippocampal cell cultures from the Alzheimer’s protein amyloid-beta-induced cell death.
- Juhaszova et al. Glycogen synthase kinase-3beta mediates convergence of protection signaling to inhibit the mitochondrial permeability transition core. J Clin Invest 113(11):1535-49 (2004). Murphy. Inhibit GSK-3beta or there’s heartbreak dead ahead. J Clin Invest 113(11):1526-8.
- Jope and Bijur. Mood stabilizers, glycogen synthase kinase-3beta, and cell survival. Molec Psychiatry 7:S35-45 (2002).
- Schafer et al. Inhibition of glycogen synthase kinase-3beta is involved in the resistance to oxidative stress in neuronal HT22 cells. Brain Res 1005:84-9 (2004).
Why Antioxidants in Large Randomized Trials Haven’t Shown Clear Benefits, While Observational Data Have
There has been much discussion concerning why large randomized intervention trials of vitamin E, vitamin C, or the combination have generally shown little or no benefits on cardiovascular disease, cancer, or all-cause mortality, in sharp contrast to the clear and substantial beneficial effects shown in observational studies using cells, animals, or humans, and in many human epidemiological studies. With clear mechanisms that indicate protective effects, why do you not see the expected results in the large intervention trials? Many hypotheses have been proposed, including that doses are too low, follow-up times are too short, or that antioxidants work as systems with other antioxidants, so you need more than just one or two. The authors of a new study1 propose that there are far more confounding factors than have been accounted for.
They analyzed the association of a wide range of indicators of socioeconomic factors, childhood environmental circumstances, and behavioral risk factors with plasma vitamin C and E concentrations from data collected in the British Women’s Heart and Health Study. The study included 4286 women aged 60–79 years randomly selected from 23 British towns. They found that people from poorer socioeconomic status at any time had lower vitamin concentrations. The odds of being in the highest quartile of the plasma vitamin C distribution decreased by 22% for each additional marker of adverse-life-course socioeconomic position. Results for vitamin E were similar. The association with each vitamin was independent of that of the other vitamin. Women who smoked and those who were obese had lower vitamin C and E concentrations. Those who engaged in at least one hour of exercise a week were said to report eating a low-fat diet or high-fiber diet, and those who consumed alcohol daily had higher vitamin concentrations. Women who had longer legs relative to their trunk length had higher concentrations of vitamin C and E, independent of socioeconomic and behavioral risk factors.
The researchers suggest, therefore, that “the conflicting observational and trial findings are probably the result of residual confounding caused by inadequate adjustment for the complexity of social and environmental exposures acting across the life course.” They cite a prospective cohort study that found that cardiovascular death was affected, in a cumulative fashion, by socioeconomic position and behavioral factors throughout the life course. The risk of death from cardiovascular disease was four times greater in those with the most adverse status for all socioeconomic and behavioral factors, compared with those having the most advantageous of those factors.
On the other hand, we and others have noticed that observational studies of hormone replacement therapy that have reported protective effects have largely used estradiol, the major human estrogen, while the large randomized trials that have reported little or no protection or even worsening of risk for cardiovascular disease or Alzheimer’s have largely used conjugated horse (not human) estrogens and synthetic progestins (not the same as natural human progesterone).2 Hence, these trials have not tested the natural human estrogens that provide protection to premenopausal women. Whether the available formulations of natural human estrogens provide the same protection as that enjoyed by premenopausal women has yet to be determined experimentally.
- Lawlor et al. Those confounded vitamins: what can we learn from the differences between observational versus randomised trial evidence? Lancet 363:1724-7 (2004).
- See, e.g., Shumaker et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women. JAMA 291(24):2947-58 (2004). Espeland et al. Conjugated equine estrogens and global cognitive function in postmenopausal women. JAMA 291(24):2959-68 (2004).
Connecting Alzheimer’s, Cardiovascular Disease, Parkinson’s Disease, and Type 2 Diabetes
It has become well known among those keeping up with scientific work on Alzheimer’s that the disease involves abnormal aggregated clumps of a normal protein, the infamous beta-amyloid protein. Less well known, perhaps, is that Parkinson’s disease involves abnormal aggregated clumps of another protein, alpha-synuclein, and that type 2 diabetes involves abnormal aggregated clumps of a different protein, amylin. Other examples are the prion proteins associated with variant Creutzfeldt-Jakob and mad cow disease. Recently, an aggregated protein with a similar structure (called an amyloid fibril) that is formed from clumped apolipoprotein C-II was reported in atherosclerotic plaques.1
What all these abnormal aggregations have in common is not chemical composition, but a chemical structure called fibrils. Fibrils are structures formed by proteins misfolded in such a way that they become insoluble and inclined to clump together, forming abnormal aggregations that are difficult to remove. As is becoming clear, many proteins are susceptible to this type of misfolding, and the misfolding (of at least some proteins) becomes more common with age. The researchers who found the clumped apolipoprotein C-II in atherosclerotic plaques had previously reported that the scavenger receptor CD36 initiates a signaling cascade upon binding to fibrillar beta-amyloid in the brain that causes the recruitment of microglia (immune cells in the brain) and the production of inflammatory mediators. Now they find that the fibrillar apolipoprotein C-II induces a CD36 signaling cascade in human atheroma that they believe may promote atherogenesis.
In another paper,2 the authors note that “There is increasing evidence that fibrillar aggregates are not esoteric species associated with a small number of proteins, but instead are a generic form of polypeptide structure that results from the dominance of interactions involving the main chain common to all such molecules.”
Other researchers report finding CD36 to be highly expressed in the cerebral cortex of Alzheimer’s patients and in cognitively normal aged individuals with diffuse amyloid plaques (as compared to age-matched individuals without amyloid plaques).3 Interestingly, a number of substances have been shown to decrease expression of CD36, including vitamin E,4 corticosteroids, TGF-beta1 (transforming growth factor-beta1), and HDL (another good reason to have high HDL levels!).5
- Medeiros et al. Fibrillar amyloid protein present in atheroma activates CD36 signal transduction. J Biol Chem 279(11):10643-8 (2004).
- Dobson. In the footsteps of alchemists. Science 304:1259-62 (2004).
- Ricciarelli et al. CD36 overexpression in human brain correlates with beta-amyloid deposition but not with Alzheimer’s disease. Free Rad Biol Med 36(8):1018-24 (2004).
- Devaraj et al. Alpha-tocopherol decreases CD36 expression in human monocyte-derived macrophages. J Lipid Res 42:521-7 (2001).
- Febbraio et al. CD36: a class B scavenger receptor involved in angiogenesis, atherosclerosis, inflammation, and lipid metabolism. J Clin Investig 108(6):785-91 (2001).
© 2005 by Durk Pearson & Sandy Shaw