February 2003 Blog with Durk and Sandy

In questions of power, let no more be heard of confidence in man, but bind him down from mischief by the chains of the Constitution.

— Thomas Jefferson

What a glorious morning this is!

— Samuel Adams, comment to John Hancock
at the Battle of Lexington, April 19, 1775

We have it in our power to begin the world over again.

— Thomas Paine, Common Sense, 1776

FDA Folds—The First Amendment Wins After 8 Years of Battle

It was indeed a glorious morning. On December 18, 2002, Ari Fleischer announced that the president and the new FDA commissioner, Mark McClellan, had met and were announcing that the FDA would be making available much more information about the health effects of dietary supplements, as well as foods, in a new FDA initiative called Better Health Information for Consumers. See www.cspan.com for the White House briefing by Ari Fleischer for Dec. 18, 2002.

On the same day, the FDA sent out a press release, “FDA Announces Initiative to Provide Better Health Information for Consumers,” which explained how health claims can be used in labels and in advertising that meet a new “weight of the scientific evidence” standard. (Up to now, the FDA has required health claims for foods or dietary supplements to meet an as yet undefined “significant scientific agreement” standard, which virtually demanded the near certainty of a scientific consensus.) The new qualified claim would require that the manufacturer provide a credible body of scientific data supporting the claim and show that the “weight of the scientific evidence” supports the claim. The FDA could require a disclaimer to prevent any potential misleading. The FDA press release can be downloaded from www.fda.gov/bbs/topics/NEWS/2002/NEW00859.html.

The FDA also issued, on December 18, a “Guidance for Industry: Qualified Health Claims in the Labeling of Conventional Foods and Dietary Supplements.” (Copies of this document can be obtained by calling 301-436-2317 or by faxing a request to 301-436-2636 or from the Internet at www.cfsan.fda.gov/~dms/guidance.html or www.fda.gov/ohrms/dockets/default.htm.)

In their “Guidance,” the FDA reviews the events leading up to this new policy. The FDA makes it clear that this major new policy change is intended to implement the court’s rulings in Pearson v. Shalala. The FDA’s new understanding of the requirements to meet Pearson are discussed in detail and is a 180º change from their prior willful misunderstanding. The proposed changes to the FDA health-claims process were those we had long been arguing for, most recently in a 160-page Public Comment submitted to the FDA in response to their call in the Federal Register for public comments on how the FDA could regulate labels and advertising and still comply with the First Amendment (our Public Comment is available at www.emord.com).

The most exciting part of this decision to bring the FDA into compliance with the First Amendment is a consideration of the changes that will quickly occur as a result. We will almost immediately see many petitions for health claims, both by dietary supplement and food companies. Reliable health information available to consumers in the marketplace will be increased manyfold in a few years. The availability of useful information on how to reduce the risks of medical conditions and manifestations of aging will provide much needed competition with the pharmaceutical industry. That industry will have to find new models for business than merely one in which profits are made by investing huge amounts of money in developing patented blockbuster drugs that are then sold at high prices as a monopoly for limited periods of time. For example, a health claim that omega-3 fatty acids (as found, for example, in coldwater fish oils) markedly reduce the risk of cardiovascular disease (CVD), especially sudden death from CVD, will allow competition with some CVD drugs on the market at much higher prices and with much greater potential for serious adverse side effects.

In ten years, we doubt that much will remain of the conventional foods that are most of what you find in a modern supermarket or fast food emporium. Instead you will find functional foods, that is, foods in which particular natural ingredients with healthful properties are increased and undesirables are reduced, either by fortification or by breeding or genetically engineering new and better forms of edible animals and plants. Biotechnology will win over consumers not by saving farmers money on pesticide use, but by making foods more healthful. For example, some scientists have already developed a tomato that contains greatly increased levels of lycopene, and we have reported previously on the high-amylose-starch potato created by genetic engineering that results in a slowly digested potato with a greatly reduced glucose spike.

In sum, this new policy will help create and expand a free market in medicine.

Loose ends? Yes, there always are some. We will not be finished with the FDA until it allows health claims for foods and dietary supplements that can be used to treatdiseases, not just help prevent diseases. This, too, is a First Amendment issue. If information on a treatment use for a dietary supplement or food is truthful and nonmisleading, then the government has no authority to prohibit it. Yet the FDA still stands firm against such treatment claims. We can expect the pharmaceutical industry to continue to fight these claims. A suit has already been filed on these issues. A health-claims petition had originally been filed by Dr. Julian Whitaker, ourselves, and others that asked the FDA to approve a claim that saw palmetto could reduce the symptoms of mild benign prostatic hypertrophy. The claim is truthful and nonmisleading, yet the FDA refused even to review the claim, saying that this is a “treatment” claim and, hence, was not covered by the DSHEA’s provisions for health claims. The DSHEA, however, permits truthful claims for “any nutrient-disease relationship.” Moreover, if the Congressional statute did not permit truthful “treatment” claims, then it would be unconstitutional, being a violation of the First Amendment. The case, where we sued the FDA on both statutory and First Amendment grounds for its unwillingness to review the saw palmetto health claim, is now awaiting decision before a judge of the district court of the District of Columbia. If we lose, then we’ll appeal. Presumably the FDA will do the same if it loses. The final loose end is this: As we interpret it, the First Amendment (“Congress shall make no law . . . abridging the freedom of speech, or of the press . . .”) provides that we need no go-ahead or authorization or approval from the government in order to communicate truthful, nonmisleading information. We shouldn’t need to ask the FDA’s permission before speaking. But we feel that it will take another two or three Clarence Thomases—Clarence Thomas believes that “commercial speech” should receive as much First Amendment protection as any other kind of speech—on the U.S. Supreme Court before we can win this.

Our heartfelt thanks to our coplaintiffs,* especially Julian Whitaker, M.D., in this 8-year and continuing litigation effort and to Jonathan Emord for making this great victory possible with his brilliant legal skills and principled commitment to the First Amendment. Plus our special thanks to those of you who are not coplaintiffs but who donated money to help us pay for this protracted battle; we hope you will feel now that it was worth every penny. We are about to enter a wonderful new world where it will be far easier to live a very long and healthy life.

Garlic and Scallion Lovers, Rejoice! Allium Vegetables Reduce Risk of Prostate Cancer

A new population-based, case-control study¹ conducted in Shanghai, China, reports strong associations of increased eating of allium vegetables (including garlic, scallions, onions, chives, and leeks) with a reduced risk of prostate cancer. The study involved 238 case subjects with confirmed prostate cancer and 471 male population controls. Men in the highest of three intake categories of total allium vegetables (greater than 10 grams/day) had a statistically significantly lower risk of prostate cancer [odds ratio (OR) = 0.51, 95% confidence interval 0.34 to 0.76, p < 0.001] than those in the lowest category (less than 2.2 grams/day). Comparison for garlic showed that the men in the highest intake category (greater than 2.14 grams/day), as compared to the lowest intake category (0 gram/day), had OR = 0.47, 95% confidence interval 0.31 to 0.71, p < 0.001. Scallions showed the greatest reduction in this study, with men in the highest intake category (greater than 2.14 grams/day) having OR = 0.30, 95% confidence interval 0.18 to 0.51, p < 0.001.

Garlic was the most commonly consumed allium vegetable, followed by scallions and Chinese chives, with median intakes of 5.9, 2.6, and 2.5 grams/day, respectively.

While scallions had the most pronounced effect, followed by garlic, men in the highest category of chives and onions experienced nonsignificant risk reductions. While onion consumption was reported to be higher in Western populations, Shanghai-population control subjects reported consuming at least 6 grams (about 2 cloves) of garlic a week. D & S comment: From our point of view, 2 cloves of garlic a week is not very much. We always liked it, and as the evidence for its health benefits has accumulated, so has the amount of garlic we consume. We now probably eat at least 7 or 8 cloves each a week.

The researchers found that the reduced risk of prostate cancer associated with the allium vegetables was independent of body size, intake of other foods, and total calorie intake. The reduced risk was also more pronounced for men with localized rather than advanced prostate cancer.

References

Hsing et al. Allium vegetables and risk of prostate cancer: a population-based study. J Natl Cancer Inst 94(21):1648-51 (2002).

Tea Enhances Insulin Activity

Green tea has been reported to have antidiabetic effects, but human studies have failed to detect consistent effects in changes in blood glucose.¹ Streptozotocin mice, a model of human diabetes, treated with various types of green, oolong, and black tea show lowered levels of blood glucose.

Tea catechins inhibit alpha-amylase

The active components in tea that cause the reduced glucose levels in animals are not known, but epicatechin gallate was shown to have the greatest activity of the catechins in lowering glucose uptake by Caco-2 cells. Epicatechin gallate was also reported to inhibit glucose uptake in the brush border membrane vesicles from rabbit small intestine. Most interesting, however, is the fact that catechins have been shown to inhibit enzymes that hydrolyze carbohydrates, including alpha-amylase, a major starch-digestive enzyme that converts starch to glucose. This may explain at least in part why a mixture of green tea catechins suppressed increases in blood glucose and insulin following carbohydrate ingestion in rats.¹ Moreover, in another study cited in this paper, humans ingesting 50 grams of starch following consumption of 200–500 mg of tea catechins had a suppression of the elevation of glucose and insulin levels. Intestinal glucose uptake is reported to be markedly inhibited by green tea polyphenols, especially those polyphenols having galloyl residues.

The authors¹ performed a rat study on the effects of green tea on insulin activity. They evaluated the insulin-potentiating activity of approximately 40 black, green, and oolong teas and found all to enhance insulin activity in the insulin-potentiating epididymal fat-cell assay. Instant teas were not found to have such activity except for one brand (not named). They found the most active green tea constituent in potentiating insulin action to be epigallocatechin, but tannins, theaflavins, and epicatechin gallate were also found to have insulin-enhancing activity and to account, the authors stated, for the number of fractions of black tea that had insulin-enhancing activity.

Milk added to tea inhibited in vitro insulin potentiation

Milk (2%) was found to inhibit the tea insulin potentiation when used at about 1 teaspoon per cup (237 ml), decreasing activity by roughly 33%. Nondairy creamers also decreased insulin-enhancing activity. The decreased insulin-enhancing effects of milk and nondairy creamers was due to the precipitation of epigallocatechin, gallocatechin gallate, and epicatechin gallate. However, the researchers also cited another paper² in which it was reported that drinking a mixture of tea and milk did not reduce the bioavailability of the tea catechins. They suggest that perhaps the catechin-milk complexes dissociate and allow the tea catechins to be absorbed. Yet another paper³reported that the antioxidant potential of tea alone or tea plus lemon was greater than that observed when milk was added to tea.

The authors propose that one possible reason why previous studies of humans drinking tea have not found reduced glucose levels is that more effective insulin could lead to lower levels of insulin with no changes in glucose. They note that in a recent study they performed using chromium, they observed no changes in glucose clearance but a very significant effect on circulating insulin. They also note that polyphenols are very rapidly cleared from the blood; hence, measuring glucose levels after an overnight fast would likely yield no effect of tea consumption because the half-life in humans for epigallocatechin gallate is less than 6 hours, and those for epigallocatechin and epicatechin are less than 4 hours.

References

Anderson, Polansky. Tea enhances insulin activity. J Agric Food Chem 50:7182-6 (2002).
van het Hof et al. Bioavailability of catechins from tea: the effect of milk. Eur J Clin Nutr 52:356-9 (1998).
Tewari et al. Comparative study of antioxidant potential of tea with and without additives. Indian J Physiol Pharmacol 44:215-9 (2000).

Why Antioxidants Do Not Necessarily Prevent Aging Due to Free Radicals

While antioxidants have been shown to have many healthful properties and may reduce the risk of cancer and atherosclerosis, most studies with antioxidants have not found antioxidants to determine maximum lifespan. When tissue antioxidants were directly compared to maximum lifespan potential (MLSP) of various species, 10 out of 12 independent investigations by seven different laboratories found that endogenous antioxidant enzymes and low-molecular weight antioxidants are negatively correlated with maximum longevity, while two other studies found no correlation.¹ A review paper proposes that this evidence strongly suggests that the rate of oxygen radical generation in tissues, rather than the antioxidant capacity, is what limits lifespan.¹

The review authors provide evidence that supports this hypothesis. They note that in 16 studies on lifelong experimental modifications of antioxidant levels by dietary supplements, pharmacological methods, or transgenic techniques performed in large numbers of animals, four found some increase in MLSP, whereas in the other 12, MLSP did not change.¹ They note that an increase in mean lifespan was a much more frequent finding in these and other studies of this type that they cited. Hence, they suggest that antioxidants can nonspecifically prevent causes of death that result in premature death, but are not likely to be effective in extending maximum lifespan.

The rate of generation of free radicals by mitochondria has been identified by these and many other researchers (including Dr. Denham Harman, originator of the free radical theory of aging) as a likely major cause of aging. Indeed, caloric restriction in rodents markedly decreases free radical generation by mitochondria but does not have a consistent effect on antioxidant capacity. Long-lived animals have been found to have constitutively lower levels of antioxidants than short-lived animals because their mitochondria generate low levels of free radicals.¹ Hence, a better strategy for increasing maximum lifespan than simply taking antioxidants that sop up excess free radicals is to take supplements that are actually capable of reducing the generation of free radicals by mitochondria.

One way that cells reduce mitochondrial free radical generation is proton leak, which is an uncoupling of the mitochondria from ATP-producing pathways, while allowing protons that would have been involved in those pathways to instead move across the mitochondrial inner membrane, releasing heat. Thermogenesis is not the only purpose of proton leak, however, since even ectotherms such as reptiles have proton leak.* It is proposed in a fascinating paper² that proton leak is a major mechanism for controlling mitochondrial free radical generation and may be a key to longevity. The paper’s author²notes that the futile cycle of proton pumping and proton leak is responsible for 20–25% of respiration in rat liver cells, while in perfused rat muscle it is 35–50% of respiration. They also note that the proportion of respiration of mammalian liver cells devoted to proton leak is remarkably constant at about 20% in a wide range of species of diverse sizes.

Proton leak is metabolically expensive, since so much caloric fuel is “wasted” by mitochondria by this means, i.e., it is not used to make ATP, but is dissipated. Hence, this mechanism must serve very important purposes, e.g., to control free radical production, damage, and possibly aging. Mitochondrial uncoupling proteins are part of the regulatory process of this proton pumping. It is known that in brown adipose tissue, uncoupling protein 1 (UCP1) is involved. Whether uncoupling protein 2 or 3 (UCP2 and UCP3), which are UCP1 homologs, are also involved in this process is controversial; they may be mild uncouplers.^2,3

Some flavonoids that have been tested have been shown to uncouple mitochondrial respiration.^3,4 Quercetin, for example, was shown in one study to be an inhibitor of the mitochondrial membrane permeability transition (MMPT), the opening of an unselective pore elicited by calcium or prooxidants. MMPT is inhibited by uncouplers of oxidative phosphorylation.³ Conjugated linoleic acid (CLA) has been reported to increase the expression of UCP2 in the mammary gland, brown adipose tissue, and white adipose tissue of mice, while UCP3 levels in skeletal muscle were significantly increased.⁵ Olive oil feeding induced the highest UCP1, UCP2, and UCP3 mRNA expression in rat interscapular brown adipose tissue, as compared to sunflower oil, palm oil, and beef tallow. In fact, olive-oil-fed rats had an increased total-body oxygen consumption as compared to the other oils.⁶ This is a likely factor in the healthful effects of the “Mediterranean diet.”

The bottom line is that this new perspective does not undermine the free radical theory of aging; in fact, it supports it. Taking the right amounts of the right antioxidants is still a good idea, but in the long run, it appears it will be necessary to reduce the free radicals created by mitochondria to increase maximum lifespan.

*In fact, even plants use this process to protect against the damage that can be caused by absorbing solar energy that exceeds that which can be used in photosynthesis. Under extreme conditions, such as icy winters or scorching summers, many evergreens can, while maintaining their light-absorbing chlorophyll, suspend growth and photosynthesis and thermally dissipate virtually all of the light energy they absorb. See Demmig-Adams and Adams, Antioxidants in photosynthesis and human nutrition. Science 298:2149-53 (2002).

References

Barja. Rate of generation of oxidative stress-related damage and animal longevity. Free Rad Biol Med 33(9):1167-72 (2002).
Brand. Uncoupling to survive? The role of mitochondrial inefficiency in ageing. Exp Gerontol 35:811-20 (2000).
Santos et al. Effect of naturally occurring flavonoids on lipid peroxidation and membrane permeability transition in mitochondria. Free Rad Biol Med 24(9):1455-61 (1998).
Stenlid. Flavonoids as inhibitors of the formation of adenosine triphosphate in plant mitochondria. Phytochem 9:2251-6 (1970).
Ealey et al. Effects of dietary conjugated linoleic acid on the expression of uncoupling proteins in mice and rats. Lipids 37(9):853-61 (2002).
Rodriguez et al. Olive oil feeding up-regulates uncoupling protein genes in rat brown adipose tissue and skeletal muscle. Am J Clin Nutr 75:213-20 (2002).

Neuroprotection, IGF-1, and Alzheimer’s Disease

A new paper in Nature Medicine¹ reports that serum IGF-1 regulates brain amyloid-beta levels. This is a hitherto unreported effect of IGF-1, though it has been known that IGF-1 is required for the neuroprotective effects of exercise on the brain and that it modulates adult neurogenesis and increases neuronal excitability.¹

As the authors note, insulin is known to modulate cellular clearance of amyloid-beta, and IGF-1 protects neurons against amyloid-beta’s toxic effects. In exploring the effect of IGF-1 on brain amyloid-beta levels, the researchers used aged (over 18 months) rats that already had elevated levels of amyloid-beta in the brain, and compared them to young rats. They found that IGF-1 treatment caused amyloid-beta levels in the hippocampus and cortex of the aging rats to decrease to those seen in young rats. Gliosis (the proliferation of brain glial cells) seen with aging was “eradicated.”

The researchers found that the transport of labeled albumin from the bloodstream into the cerebrospinal fluid (CSF) was greatly enhanced with IGF-1 treatment. Hence, they hypothesize that this might explain the increased amyloid-beta clearance, since amyloid-beta might be transported out of the brain by albumin, to which it is known to bind, or by other serum proteins.

The other particularly interesting finding in this study is that TNF-alpha (tumor necrosis factor-alpha, an inflammatory cytokine) antagonized the stimulatory effects of IGF-1 on amyloid-beta clearance. This is just another good reason to reduce fat stores. Fat cells (adipocytes) are known to synthesize and release TNF-alpha into the circulation. Substances known to suppress TNF-alpha include nonsteroidal anti-inflammatory drugs (NSAIDs),² estrogen,³ alpha-lipoic acid,⁴ resistance exercise,⁵ quercetin,⁶ N-acetylcysteine, thalidomide, and pentoxifylline.

References

Carro et al. Serum insulin-like growth factor 1 regulates brain amyloid-beta levels. Nature Med 8(12):1390-7 (2002).
Joussen et al. Nonsteroidal anti-inflammatory drugs prevent early diabetic retinopathy via TNF-alpha suppression. FASEB J (Jan. 30, 2002).
Cenci et al. Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-alpha. J Clin Invest 106(10):1229-37 (2000). Walsh et al. 17-beta-Estradiol reduces tumor necrosis factor-alpha-mediated LDL accumulation in the artery wall. J Lipid Res 40:387-96 (1999).
Zhang, Frei. Alpha-lipoic acid inhibits TNF-alpha-induced NF-kappaB activation and adhesion molecule expression in human aortic endothelial cells. FASEB J 15:2423-32 (2001).
Greiwe et al. Resistance exercise decreases skeletal muscle tumor necrosis factor alpha in frail elderly humans. FASEB J 15:475-82 (2001).
Wang, Mazza. Effects of anthocyanins and other phenolic compounds on the production of tumor necrosis factor alpha in LPS/IFN-gamma-activated RAW 264.7 macrophages. J Agric Food Chem 50:4183-9 (2002).