February 2009 Blog with Durk and Sandy

Happy New Year! Live Long & Prosper!!

The best definition of an immortal is someone who hasn’t died yet.

— Tom Holt, Ye Gods! (1992)

It sounded logical—but I could not forget Kettering’s Law: ‘Logic is an organized way of going wrong with confidence.’

— Robert A. Heinlein, The Number of the Beast (1980)

On its world the people are people. The leaders are lizards. The people hate the lizards and the lizards rule the people. Odd, said Arthur. I thought you said it was a democracy. I did, said Ford. [. . .] You mean they actually vote for the lizards? Oh, yes, said Ford with a shrug, of course. But, said Arthur, going for the big one again, why? Because if they didn’t vote for a lizard, said Ford, the wrong lizard might get in.

— Douglas Adams, So Long, and Thanks for All the Fish (1985)

Above quotes from Science Fiction Quotations edited by Gary Westfahl, Yale University Press (2005)

L-Arginine Prevents Metabolic Effects of High Glucose in Diabetic Mice

High glucose levels and blood lipids are responsible for most of the negative effects of diabetes and increasing levels of glucose and lipids also contribute importantly to the aging process. A new paper¹ reports that L-arginine supplementation (delivered via subcutaneous osmotic pumps) of 50 mg/kg/day in diabetic (insulin-deficient—type 1—diabetes induced by streptozotocin) mice “markedly prevented tissue sorbitol accumulation, ROS [reactive oxygen species] generation, and PKC [protein kinase C] activation—three critical biochemical abnormalities associated with hyperglycemic injury. Taken together, these results support the novel concept that NO [nitric oxide] production or availability during diabetes is a key step that is mechanistically linked to the major biochemical effects of high glucose.”¹

The untreated diabetic mice had 2- to 2.4-fold higher levels of plasma triglyceride than the non-diabetic controls. L-arginine treatment reduced the plasma triglycerides of the diabetic mice to levels not significantly different than that of the controls. While the diabetic animals had significantly increased (1.3-fold compared to controls) circulating levels of soluble intercellular adhesion molecule, a marker of vascular inflammation, this was completely prevented by L-arginine.

L-arginine also completely abolished the accumulation of sorbitol (increased by 5.8-fold in the kidneys of the diabetic mice), by inhibiting aldose reductase, an enzyme that catalyzes the first and rate-limiting step of the polyol pathway that creates sorbitol from glucose.

The authors explain that activation of PKC, particularly the PKCbetaII isoform, “has been associated with several features of glucose toxicity, including microvascular changes, increased vascular ROS generation, and endothelial and macrophage activation. In particular, hyperglycemia-induced endothelial dysfunction [failure of blood vessels to dilate to response to physiological stimuli such as acetylcholine] in humans is prevented by pretreatment with the PKCbetaII-specific inhibitor ruboxistaurin. Hence, our observation that increasing NO by simple L-arginine supplementation prevents PKC activation supports the underlying hypothesis that AR [aldose reductase] plays a critical role in the early stages of diabetic complications and that inhibition of this enzyme by increasing NO prevents one of the major causes of diabetic complications, i.e., PKC activation.”¹

Scaled as a percentage of the diet of these mice, this is roughly equivalent to 250 mg of supplemental arginine for a human. Scaled by body weight, this is 5 grams of supplemental arginine per day for a 100 kg human.

We get our supplemental L-arginine from InnerPower Plus™, our formulation of NO pathway constituents that includes arginine (6 grams per serving) and citrulline plus factors that affect pathways that crosstalk (interact) with the NO pathway, including choline.

Reference

1. West et al. L-Arginine prevents metabolic effects of high glucose in diabetic mice. FEBS Lett 582:2609-14 (2008).

At the establishment of our Constitutions, the judiciary bodies were supposed to be the most helpless and harmless members of the government. Experience, however, soon showed in what way they were to become the most dangerous; that the insufficiency of the means provided for their removal gave them a freehold and irresponsibility in office; that their decisions, seeming to concern individual suitors only, pass silent and unheeded by the public at large; that these decisions, nevertheless, become law by precedent, sapping, by little and little, the foundations of the Constitution, and working its change by construction, before any one has perceived that that invisible and helpless worm has been busily employed in consuming its substance. In truth, man is not made to be trusted for life, if secured against all liability to account.

Fatty Acid Synthase as a Target for Antiviral Therapy

Fatty acid synthase is an interesting enzyme. Not only does it control the last step in the synthesis of fats, but it is known to be required by many types of human cancer. A new paper¹ now reports that upregulation of host fatty acid biosynthesis by increasing host fatty acid synthase expression is required for replication by two enveloped viruses, human cytomegalovirus and influenza A.* This was determined by utilizing inhibitors of fatty acid synthase (C75) or ACC (acetylCoA carboxylase) (TOFA) and finding that these two enzymes, carrying out the last two steps of fatty acid synthesis, are required for replication by the two viruses.

 

---

*E.g., the viruses hijack host fatty acid synthase, without which they cannot reproduce.

 

---

 

Fatty acid synthase (FAS) inhibitors are found in some plants (perhaps in part to protect against enveloped viruses like those above), such as certain varieties of tea (Camellia sinensis). Our ShapeShifter Teas™ were specifically designed with combinations of teas that have FAS inhibitory properties for help with weight loss and weight maintenance. We have personally observed noticeable symptomatic relief during viral infections from increasing our consumption of tea.

For more on the effects of ShapeShifter Teas on FAS, see “Cocktail of Selected Teas for Better Health and Weight Loss” in the April 2007 issue of Life Enhancement magazine.

Reference

1. Munger et al. Systems-level metabolic flux profiling identifies fatty acid synthesis as a target for antiviral therapy. Nat Biotechnol 26(10):1179-86 (2008).

 

Cysteine Decreases Expression of Genes Involved in Liver Cell Fatty Acid Synthesis

Sterol regulatory element-binding protein (SREBP)-1c has been found to be a key transcription factor for the expression/regulation of lipogenic (fat producing) enzyme genes such as fatty acid synthase (FAS), glucose-6-phosphate dehydrogenase (G6PDH) and stearoyl-coenzyme A desaturase (SCD) in liver (but not adipocytes) cells.^1,2 A new cell culture study shows that the amino acid L-cysteine reduces (down-regulates) SREBP-1c regulated lipogenic enzymes expression in liver cells by increasing glutathione levels in the cells.² The study was done using human hepatoma (HepG2) cells that were exposed to various concentrations of L-cysteine.

Oxidative stress has been reported to increase the activity of SREBP-1c in human liver cells.³ ROS (reactive oxygen species) have also been found to be critical mediators of insulin-dependent lipogenesis.^3a L-cysteine is required for and is usually the limiting amino acid in the synthesis of glutathione, one of the most important endogenous antioxidant defense molecules. In this study,¹ exposure of cells to 5 mM L-cysteine was reported to reduce the mRNA concentration of SREBP-1c (–35 to –43%) and its target genes fatty acid synthase (FAS; –20 to –50%); glucose-6-phosphate-dehydrogenase (G6PDH, –31 to –35%); and stearoyl-coenzyme A desaturase (SCD)1 by –34 to –50%.²Moreover, the cells treated with L-cysteine had 47% higher glutathione and 47% lower triglyceride concentrations than control cells. In experiments where cells were treated with both L-cysteine and an inhibitor of glutathione synthesis, no downregulation of the lipogenic genes was seen, showing that the effect was mediated by increased glutathione. Treatment with an oxidant (CuSO4) upregulated the activity of the lipogenic enzymes compared to control cells, but concurrent treatment of L-cysteine with the oxidant caused gene expression to remain at the control level.

As we have mentioned before, both of us take an L-cysteine supplement called Root Food™ (both for its glutathione-synthesis supporting effects and because large amounts of cysteine are required for hair synthesis). We are very happy to learn of this important effect of L-cysteine in helping limit the oxidative stress that increases fat synthesis in the liver. Cysteine is also a limiting nutrient for the liver synthesis of metallothionines, molecules which help to detoxify and excrete heavy metals, many of which are free radical catalyst pro-oxidants.

Another study⁴ reported that mice fed with a diet containing fish oils at a level of 10% of energy intake had levels of SREBP-1 protein decreased by 50% (compared to controls) with concomitant reductions of lipogenic enzymes. “These data suggest that physiological doses of fish oil feeding effectively decrease expression of liver lipogenic enzymes by inhibiting SREBP-1 proteolytic cascade . . .”⁴

References 
1. Sekiya et al. SREBP-1-independent regulation of lipogenic gene expression in adipocytes. J Lipid Res 48:1581-91 (2007). 
2. Bettzieche et al. L-cysteine down-regulates SREBP-1c-regulated lipogenic enzymes expression via glutathione in HepG2 cells. Ann Nutr Metab 52:196-203 (2008). 
3. Sekiya et al. Oxidative stress induced lipid accumulation via SREBP1c activation in HepG2 cells,” Biochem Biophys Res Commun 375:602-7 (2008). 
3a. Berniakovich et al. p66Shc-generated oxidative signal promotes fat accumulation. J Biol Chem 283(49):34283-93 (2008). 
4. Nakatani et al. A low fish oil inhibits SREBP-1 proteolytic cascade, while a high fish oil feeding decreases SREBP-1 mRNA in mice liver: relationship to anti-obesity. J Lipid Res 44:369-79 (2003).

Slowing Aging by De-AGEing: Western Diets Contain 
High Levels of Fat and Also of AGEs

As the study of advanced glycation endproducts (AGEs) proceeds, more information is being revealed about the deleterious effects of ubiquitous dietary content of AGEs and their precursors, as well as the health and longevity benefits of reducing them. New papers looked at the effect of dietary AGE content on the results of caloric restriction in mice, mediation of cardiac inflammation by AGEs in a Western-style diet [e.g., high (21%) fat], and inhibition of protein glycation (which proceeds to AGEs) by extracts of culinary herbs and spices. Do your health a favor that you will definitely not get from any government-funded healthcare program by reducing your intake of AGEs.

A research group published a new paper¹ testing the hypothesis that consumption of a reduced calorie diet, which also reduces the consumption of dietary AGEs, might mean that some of the beneficial effects of caloric restriction (CR) are due to AGE restriction. The researchers created an increased AGE version of a CR diet by increasing the heat exposure of the diet by 15 minutes at 120°C, which contained AGE levels similar to those ingested in the regular (Reg) diet fed ad lib to another group of mice in the experiments.

Lifespan Effects of CR Erased by High AGEs

Compared to control CR mice (eating the basic CR diet without the additional heat treatment-created AGEs), the CR-high (higher in AGEs) group had a shorter lifespan than even the mice on the ad lib Reg diet. The higher AGEs also increased oxidant load and depleted antioxidant defenses. Old CR-high mice developed high levels of 8-isoprostanes (marker of oxidant stress), AGEs, RAGE (receptor for AGEs), and lower GSH/GSSG levels (lower reduced-glutathione levels), as well as insulin resistance, marked heart and kidney fibrosis.

Cardiac Inflammation Occuring on A Western-type Diet Mediated by Activation of RAGE by AGEs

Another new paper² reports that a high fat Western-type diet is also high in AGEs. They examined the effects of a high fat “fast food” (21% fat) diet in intact mice and also in mice with RAGE (AGE receptor) knocked out. A group of the intact mice fed the high fat high AGEs diet were also treated with an AGE inhibitor drug, alagebrium chloride.

The Western-style diet was associated in the intact mice with cardiac hypertrophy, inflammation, mitochondrial-dependent superoxide radical production, and cardiac AGE accumulation. The RAGE KO (knockout) mice on the diet similarly became obese and accumulated intramyocardial lipid, but the cardiac hypertrophy, inflammation, and oxidative stress were attenuated compared with the intact mice. Both the intact mice and the RAGE KO mice receiving the AGE inhibitor drug had reduced levels of inflammation and oxidative stress. The authors conclude that “[t]his study suggests that AGEs represent important mediators of cardiac injury associated with a Western fast-food diet.”

Inhibition of Glycation by Extracts of Culinary Herbs and Spices

The benefits of certain herbs and spices are reported in another new paper³ to include inhibition of protein glycation (in this study, the sugar used was fructose, which (like glucose) also forms glycation (AGE) products but is actually more reactive than glucose.³

Of the many herbs and spices studied, cloves was the most potent in inhibiting the glycation of albumin, followed by cinnamon. Other effective herbs included sage, marjoram, tarragon, and rosemary.

Inhibiting the Formation of AGEs with Nutrients

We use lower heat food preparation methods, such as slow cooking at a low setting, to reduce cooking-induced creation of AGEs. In addition, we also take a formulation (AGEless™) containing a group of nutrients that potently inhibit the formation of AGEs within the body; these include rutin, carnosine, histidine, benfotiamine, and alpha-lipoic acid. See “Reducing Glycation Reactions for Better Health and Longer Life” in the February 2008 Life Enhancement magazine.

References

1. Cai et al. Oral glycotoxins determine the effects of caloric restriction on oxidant stress, age-related diseases, and lifespan. Am J Pathol 173(2):327-36 (2008).
2. Tikellis et al. Cardiac inflammation associated with Western diet is mediated via activation of RAGE by AGEs. Am J Physiol Endocrinol Metab 295:E323-30 (2008).
3. Dearlove et al. “Inhibition of protein glycation by extracts of culinary herbs and spices,” J Med Food 11(2):275- 81 (2008).

 

Beta-alanine Supplementation Augments Muscle Carnosine Content and Improves Muscular Performance

Carnosine (a dipeptide synthesized from the amino acids histidine and beta-alanine) is present in relatively high concentrations in muscle and the brain. Several studies have suggested that muscle carnosine is a determining factor in high-intensity dynamic and isometric exercise performance in both trained and untrained men and women.^1,2,3One recent paper¹ reported that beta-alanine is the rate-limiting factor required for endogenous (in the body) carnosine synthesis.

One problem with taking carnosine orally to improve muscular function is that it has a very short half life due to the presence in the plasma of the enzyme carnosinase that breaks it down into its two amino acid constituents. However, supplements of beta-alanine, acting as the rate-limiting carnosine precursor, increases intracellular carnosine levels and has beneficial effects on muscle fatigue, especially on the fast-twitch (glycolytic) type of muscle fibers associated with maximum power (such as sprints).²

In a recent paper,² men who took 4 grams to 6.4 grams of beta-alanine a day (in divided doses) for 4 weeks had significantly improved exercise performance, including increased ability to sustain power output in the final 10 seconds of a 30 second Wingate test (high-intensity exercise). There was a 13.0% increase in TWD (Total Work Done) after 4 weeks, with a further 3.2% increase at 10 weeks. TWD was unchanged at 4 and 10 weeks in the control subjects. The 4 to 6.4 grams of beta-alanine used as supplementation in this study was estimated by the researchers to be 1–2 times greater than that found in some human diets.² In this paper, the authors attributed the beneficial effects of beta-alanine-induced increases in carnosine to carnosine’s buffering capacity of acid produced in muscles by exercise.

Another recent paper¹ reported that beta-alanine supplements (4.8 g. per day) in trained male sprinters increased muscle carnosine content and slightly but significantly attenuated fatigue in repeated bouts of exhaustive dynamic contractions. Endurance (400 meter race time) did not improve.

A different recent paper³ reported that 28 days of beta-alanine supplementation in women in a cycle ergometry test increased the time to fatigue and ventilatory threshold (a measure of the respiratory response to the increased production of carbon dioxide with exercise) and increased the time-to-exhaustion at submaximal workloads. Maximal aerobic power was not affected by beta-alanine. 3.2 grams/day of beta-alanine was taken by subjects during days 1 to 7; 6.4 grams/day of beta-alanine was the dose ingested during days 8 to 28.

The Bottom Line

“Currently it would appear that a minimum effective dose of 65–86 mg/kg/day is needed for performance enhancement in young men and women.”³ [Emphasis added] Our FoldRight™ contains 2 grams of beta-alanine in the recommended four servings a day. That plus the amount of beta-alanine from dietary ingestion of protein, especially meat, could reach this estimated minimum effective dose range.

References

1. Derave et al. Beta-alanine supplementation augments muscle carnosine content and attenuates fatigue during repeated isokinetic contraction bouts in trained sprinters. J Appl Physiol 103:1736-43 (2007).
2. Hill et al. Influence of beta-alanine supplementation on skeletal muscle carnosine concentrations and high intensity cycling capacity. Amino Acids 32:225-33 (2007).
3. Stout et al. Effects of beta-alanine supplementation on the onset of neuromuscular fatigue and ventilatory threshold in women. Amino Acids 32:381-6 (2007).

 

Resveratrol, at Concentrations Attainable by Moderate Wine Consumption, Increases NO Production

Though much has been published on the beneficial effects of resveratrol, relatively less has focused on the effects of the small concentrations you can actually get with moderate wine consumption. A new study¹ reports on just that.

Twenty healthy subjects were randomized to consume either 300 mL/day of red or white wine during dinner. The red wine, consumed by 4 male and 6 female subjects, mean age 45 ± 6 years), had a total polyphenolic concentration of 1.8 g/L. White wine was consumed by 5 male and 5 female subjects (mean age 42 ± 5 years) and had a total polyphenolic concentration of 0.25 g/L. (There were no subjects who didn’t ingest wine.)

Experimental (ex vivo and in vitro) results were derived from studies on platelets obtained from the subjects’ plasma.

Plasma resveratrol concentration increased from 0.72 ± 0.3 to 1.33 ± 0.3 μmol/L for white wine and from 0.71 ± 0.2 to 1.72 ± 0.1 μmol/L for red wine. Nitrite plus nitrate concentrations in the supernatant of arachidonic acid-stimulated platelet-rich plasma increased significantly after 15 days of controlled red [from 13.9 ± 3.4 μmol/L to 24.1 ± 3.6 μmol/L (P=0.037)] or white [from 10.6 ± 2.4 μmol/L to 19.8 ± 4.8 μmol/L(P=0.01)], indicating increased platelet NO production.

In vitro studies with platelets showed, among other findings, that preincubation with resveratrol (0.1–0.5 μmol/L decreased arachidonic acid-mediated superoxide radical formation, with a significant reduction reported at concentrations of at least 0.1 μmol/L, e.g., achievable with moderate wine consumption. In addition, activated p38 MAPK, a strong producer of ROS (reactive oxygen species) and inducer of platelet activation, was also decreased in resveratrol-preincubated platelets.

The authors conclude that “[t]his activity may contribute to the beneficial effects of moderate wine intake on ischemic cardiovascular disease.”

Do the results of this study mean that, if one is already consuming moderate amounts of wine that a resveratrol supplement in addition would be of no further value? Not necessarily. It is not clear yet what the optimum amount of resveratrol is and how that would vary under different conditions of health. The two of us do take extra resveratrol as contained in our MealMate™ weight control supplement.

Reference

1. Gresele et al. Resveratrol, at concentrations attainable with moderate wine consumption, stimulates human platelet nitric oxide production. J Nutr 138:1602-8 (2008).

Absorption of Sulforaphane in Humans Higher After 
Consuming Raw As Opposed to Cooked Broccoli

One of the important health-promoting constituents of broccoli, cauliflower, and other cruciferous vegetables is the isothiocyanate, sulforaphane. Animal studies have shown sulforaphane to be a potent anti-carcinogen that is proposed to work by inhibiting carcinogen-activating phase 1 biotransformation enzymes, inducing phase II detoxification enzymes, anti-inflammation, and induction of apoptosis (programmed cell death).¹

A new study¹ reports that, in eight men who ate 200 grams of crushed broccoli, either raw or cooked, with a warm meal in a randomized free-living open cross-over trial, sulforaphane was found in significantly greater amounts in the blood and urine of those who ate the raw as compared to the cooked broccoli. The bioavailability of sulforaphane was reported to be 37% after raw broccoli consumption as compared to 3.4% after cooked broccoli consumption. The absorption of sulforaphane was also delayed after eating cooked broccoli, with peak plasma levels for sulforaphane reached at 6 hours for cooked versus 1.6 hours for raw broccoli.

Phase II Detoxification Pathway to Better Health

The induction of phase II enzymes has been reported in many animal studies to promote important health-protective effects (for example, anti-inflammation,^1asuppression of neuron loss in a fruit fly model of Parkinson’s disease,² hypolipidemic effects of green tea,³ silibinin in cancer chemoprevention,⁴ protection against chemical carcinogenesis by curcumin,⁵ and healthier aging.⁶ Phase II enzyme inducers include, in addition to those found in cruciferous vegetables, black tea,⁷ green tea,³ green onion,⁸ BHT,^1a and anthocyanins (the blue and purple colored substances found in, for example, berries).⁹

References 
1. Vermeulen et al. Bioavailability and kinetics of sulforaphane in humans after consumption of cooked versus raw broccoli. J Agric Food Chem 56:10505-10509 (2008)
1a. Juurlink. Therapeutic potential of dietary phase 2 enzyme inducers in ameliorating diseases that have an underlying inflammatory component. Can J Physiol Pharmacol79:266-282 (2001) 
2. Trinh et al. Induction of the phase II detoxification pathway suppresses neuron loss in Drosophila models of Parkinson’s disease. J Neurosci 28(2):465-472 (2008). 
3. Lin et al. Hypolipidemic effect of green tea leaves through induction of antioxidant and phase II enzymes including superoxide dismutase, catalase, and glutathione S-transferase in rats. J Agric Food Chem 46:1893-9 (1998). 
4. Zhao and Agarwal. Tissue distribution of silibinin, the major active constituent of silymarin, in mice and its association with enhancement of phase II enzymes: implications in cancer chemoprevention. Carcinogenesis 20(11):2101-8 (1999). 
5. Iqhal et al. Dietary supplementation of curcumin enhances antioxidant and phase II metabolizing enzymes in ddY male mice: possible role in protection against chemical carcinogenesis and toxicity. Pharmacol Toxicol 92:33-8 (2003). 
6. Noyan-Ashraf et al. Phase 2 protein inducers in the diet promote healthier aging. J Gerontol A Biol Sci Med Sci 63A(11):1168-76 (2008). 
7. Patel and Maru. Polymeric black tea polyphenols induce phase II enzymes via Nrf2 in mouse liver and lungs. Free Radic Biol Med 44:1897-1911 (2008). 
8. Xiao and Parkin. Isolation and identification of phase II enzyme-inducing agents from nonpolar extracts of green onion (Allium spp.). J Agric Food Chem 54:8417-24 (2006). 
9. Shih et al. Anthocyanins induce the activation of phase II enzymes through the antioxidant response element pathway against oxidative stress-induced apoptosis. J Agric Food Chem 55:9427-35 (2007).

 

Fed Refuses to Disclose Recipients of $2 Trillion

From a posting at Bloomberg.com, written by Mark Pittman: “The Federal Reserve refused a [Freedom of Information Act] request by Bloomberg News to disclose the recipients of more than $2 trillion of emergency loans from U.S. taxpayers and the assets the central bank is accepting as collateral.

“‘There has to be something they can tell the public because we have a right to know what they are doing,’ said Lucy Daiglish, executive director of the Arlington, Virginia based Reporters Committee for Freedom of the Press.”

Bloomberg News filed suit under the Freedom of Information Act on Nov. 7th. (Bloomberg LP v. Board of Governors of the Federal Reserve System, 08-CV-9595, U.S. District Court, Southern District of New York (Manhattan)) To contact the reporters on this story: Mark Pittman in New York at mpittman@bloomberg.net.

The Fed argued that the “trade-secret exemption [that allows withholding information under the FOIA] could be expanded to include potential harm to any of the central bank’s customers, said Bruce Johnson, a lawyer at Davis Wright Tremaine LLP in Seattle. That expansion is not contained in the freedom-of-information law, Johnson said.” [Emphasis added]

“‘If they told us what [assets] they held, we would know the potential losses that the government may take and that’s what they don’t want us to know,’” said Carlos Mendez, a senior managing director at New York-based ICP Capital LLC, which oversees $22 billion in assets.”

This is an immensely important and disquieting story. Have you read it in your newspaper or heard it on TV news?

GlaxoSmithKline and Allies Petition the FDA to Disallow Weight Loss Claims for Dietary Supplements

They never give up—the drug companies that is—trying to get the FDA to eliminate competitive products when consumers don’t buy “enough” of their own voluntarily. In this case, GlaxoSmithKline is the manufacturer of a weight loss drug, Alli^®, an over-the-counter nonprescription version of the drug orlistat (Xenical^®). Apparently, they are not happy with its sales. A recent Citizen Petition filed by GlaxoSmithKline (joined by the American Dietetic Association, the Obesity Society, and Shaping America’s Health (a sister organization of the ADA)) asks the FDA to ban weight loss claims for dietary supplements, arguing that they are (in effect) drug claims because they claim to treat excess weight which, the petitioners say, is a risk factor for many diseases. They point out that FDA doesn’t permit a dietary supplement health claim for cholesterol reduction because that might be understood as a claim to reduce heart disease risk. (Note that, under GlaxoSmithKline et al’s interpretation, one couldn’t even claim that a high fiber diet, reduced calorie intake, or a low glycemic index diet, let alone a food studied extensively for its weight loss effects, green tea, could help people lose weight.) The Petition also claims that there is no evidence that dietary supplements can cause weight loss! We filed vehement objections with the FDA in opposition to the Petition (see end of this newsletter).

If it isn’t auto companies trying to get immense amounts of taxpayers’ money now (and with the certainty of “needing” more again and again later) to support a losing business model, it is drug companies seeking to use the guns of the FDA to drive competition from the market. (To be fair, the auto companies’ “losing business model” is partly the result of federal mandates requiring that the companies build and attempt to sell small, fuel-thrifty vehicles as a large proportion of their product line, where they lose money on each sale. Another big part of the “loser business model” is acquiescence to labor demands for huge pensions and health-care benefits, pay for not working when laid off, and far higher average wages than those paid at non-unionized American auto manufacturers, such as Toyota.

The purpose of the proposed auto company bailouts is to subsidize the losing business model and to allow the federal government to add additional politically-correct federal mandates that would make it an even bigger loser; hence, large amounts of “government” money would need to be periodically injected forever (from taxes and borrowing as well as inflating the money supply). Just as Medicare is Amtrak medicine, the new GM, Ford, and Chrysler would be Amtrak Goes Wild.

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

— Franklin Delano 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.R., Radio speech, Mar. 2, 1930

October ___, 2008 
Division of Dockets Management 
Food and Drug Administration 
Department of Health and Human Services 
5630 Fishers Lane, Room 1061 
Rockville, MD 20852

 

Re: Comment in Response to Citizen Petition Requesting FDA to Treat Weight Loss Claims for Dietary Supplements as Disease Claims, filed April 17, 2008

Durk Pearson and Sandy Shaw, by counsel, hereby submit comments in response to the Citizen Petition of GlaxoSmithKline and each of the proxies that it financially backs, the American Dietetic Association; the Obesity Society; and Shaping America’s Health, who it identifies as co-petitioners.

At the outset, GlaxoSmithKline has violated the agency’s citizen petition rule, 21 CFR § 10.30, because it has not identified a conflict of interest. GlaxoSmithKline sells the over-the-counter weight loss drug Alli. Alli competes for market share with all manner of weight loss remedies, including those that come in the form of dietary supplements and those that come in the form of modified, low caloric foods, low calorie density high fiber foods, and low glycemic index foods, some of which are often sold as part of a meal plan. The problem with Alli is that it causes anal leakage, an urgent need to void, and depletes fat soluble essential nutrient stores, thus increasing the risk of nutrient deficiency related diseases such as osteoporosis; heart disease; and cancer. Those aspects as well as its limited efficacy and possibly its price have kept the product from achieving market success despite heavy promotion by GlaxoSmithKline.

In a transparent attempt to induce FDA to assist in an anti-competitive campaign to eliminate its competitors, GlaxoSmithKline now asks FDA to declare claims heretofore permitted for dietary supplements that affect weight loss (and presumably also for modified dietetic foods that affect weight loss) unlawful. GlaxoSmithKline seeks a blanket speech ban, imposing a prior restraint upon all existing and future nutrient based claims that would inform consumers of weight loss effects and potential of those products.

Ironically, GlaxoSmithKline is unwittingly inviting a boomerang effect. If, indeed, it is correct that weight is inextricably a symptom of serious disease, including type two diabetes, heart disease, cancer, metabolic syndrome, etc., which are states that require medical intervention and management, then its product Alli needs to be removed from the market. That is because Alli purports to reduce weight which, according to GlaxoSmithKline logic, is inextricably linked to serious disease; ergo, Alli should only be available by prescription; hence, off the over-the-counter market it must go lest serious disease states go undetected or, worse yet, become subject to the mistaken belief that they are self-treatable through ingestion of Alli.

GlaxoSmithKline asks the FDA to adopt a blanket speech ban. It does so based on the following syllogism which contains false representations of fact and non-sequiturs. GlaxoSmithKline argues: (1) that overweight is a contributing factor to serious disease, including diabetes, heart disease, cancer, and metabolic syndrome, among others; (2) that, thus, weight is a classic sign or symptom of disease making it ineligible for use in structure/function claims for dietary supplements (and presumably foods); (3) that no dietary supplement affects weight loss, thus making claims to that effect inherently false and misleading; and (4) that FDA may act unilaterally, without rulemaking, to reclassify all claims concerning the weight loss effects of dietary supplements (and presumably foods) as drug claims condemnable for supplements (and presumably foods) but allowable for drugs, including (and most especially) for GlaxoSmithKline’s Alli.

Factual and legal problems plague this syllogism and invite ready challenge if the FDA proves so bold that it harkens GlaxoSmithKline’s anticompetitive call with action to eliminate all weight loss claims from the supplement (and presumably the food) marketplaces to the great detriment of consumers and the sure violation of the First Amendment. Let us first consider the factual problems.

GlaxoSmithKline’s False Facts

Overweight Is Not Per Se a Sign or Symptom of Disease. GlaxoSmithKline relies on the BMI index as a standard for determining overweight status and deems overweight status per se a sign or symptom of disease. The supposition is false. Chronic overweight status at a level of ten or more pounds above the BMI may contribute to a diverse array of disease conditions but has not been shown to be a causative factor for initiation or progression of any single disease cited by GlaxoSmithKline. Overweight status that is transient or that is below a level of ten pounds above the BMI is not linked to disease of any kind. See ______________. Based on this logic, the FDA drew a distinction in its Final Rule on structure/function claims recognizing that overweight status, as opposed to obesity, is a normative condition, while the latter is a disease condition. That solves the problem nicely because while obesity (defined as a BMI of 30 or more) is itself a disease and may contribute to a host of diseases mentioned by GlaxoSmithKline; overweight status is too generalized a condition to be categorized as either a disease in and of itself or a causative factor contributing to disease. Furthermore, BMI does not distinguish between high percentages of body fat (unhealthy) and muscle (healthy). Many Olympic athletes have BMIs in the “overweight” to “obese” range.

Moreover, each disease state cited by GlaxoSmithKline is one for which there are multiple known causative factors and while overweight may contribute, it has not been shown to be the causative factor for the diseases in question. That makes overweight status an inadequate distinguishing principle, because it may also be said that aging may be a contributing factor to those same disease states, as may excess consumption of sugar, as may ingestion of excess alcohol, as may consumption of excess saturated fats in lunch meats, as may consumption of excess high fructose corn syrup in beverages. GlaxoSmithKline thus proceeds down a slippery slope that if not checked results in a wholesale transformation of the speech marketplace where almost all structure/function claims become presumptively unlawful as drug claims on the weak reed that they concern physiological processes that may under certain conditions contribute ultimately to the manifestation of disease states. This would result in a ban on all structure-function claims because all physiological processes can be, under certain conditions, part of a disease process. FDA should guard against that move because it entails direct and substantial censorship of truthful information concerning the effect of nutrients on health related conditions and will be to the grave detriment of consumers of foods and nutrients.

Even obesity is not always a sign or symptom of disease. A new paper reports that a 1999–2004 database of 5440 participants aged 20 years or older in the National Health and Nutrition Examination Survey (NHANES) that (as determined by measuring a selected set of physiological functions) approximately 29% of obese men (BMI over 30.0) and approximately 35% of obese women (BMI over 30.0) were metabolically normal. This paper also reports that approximately 30% of normal weight men (BMI less than 25.0) and approximately 21% of normal weight women (BMI less than 25.0) were metabolically abnormal. Hence, BMI alone is not a reliable indicator of whether there is disease present and, hence, overweight or even obesity cannot be, as claimed by Glaxo et al’s Citizen Petition, a per se sign or symptom of disease. See Wildman et al, “The obese without cardiometabolic risk factor clustering and the normal weight with cardiometabolic risk factor clustering: prevelance and correlates of 2 phenotypes among the US population NHANES 1999–2004,” Arch. Intern. Med. 168:1617–1624 (2008)

Dietary Ingredients And Supplements Do Affect Weight. GlaxoSmithKline makes the cavalier statement that no dietary supplement affects weight. It relies on a myopic and selective excerpting of the scientific literature to support that proposition and upon a panel having economic interests tied to GlaxoSmithKline for support. The peer-reviewed scientific evidence reveals dietary ingredients and supplements that do affect weight status. Those include green tea and black tea (which increase energy expenditure and reduce food intake); caffeine (which increases energy expenditure and reduces food intake); capsaicin (which increases energy expenditure and is synergistic with caffeine); mustard (which increases energy expenditure); high protein-low fat diets; and high fiber diets. See Exhibit A hereto (over 60 peer reviewed scientific journal articles concerning the weight loss effects of the foregoing).

Note well that FDA possesses the statutory authority to prosecute any who make false and misleading claims and has acted under that authority to address false weight loss claims for supplements. 31 U.S.C. § 342(f)(1)(A); See Hi-Tech Pharms., Inc. v. Crawford, F. Supp. 2d 1341 (N.D. GA 2007). That selective enforcement avoids the constitutional violations, described below, inherent in the blanket ban GlaxoSmithKline seeks. It achieves the objective of ensuring that consumers have available to them an entire array of truthful information concerning the effects of nutrients on weight status without restricting that information for the exclusive use of pharmaceutical companies holding FDA approved weight loss drugs.

GlaxoSmithKline’s Call for Unconstitutional Agency Action

GlaxoSmithKline asks FDA to declare all weight loss claims for dietary supplements forbidden. That blanket speech ban is presumptively unconstitutional under the First Amendment commercial speech standard. See Edenfield v. Fane, 507 U.S. 761, 769 (1993).

Moreover, the blanket ban is particularly problematic because it presumes all speech concerning weight loss effects of dietary supplements to be false. Two problems arise. First, undoubtedly some claims are true, dependent upon their wording, and second, there are obvious less speech restrictive alternatives to outright suppression: case by case enforcement and reliance on disclaimers as a less speech restrictive alternative when disclaimers can cure deceptiveness.

So, e.g., a claim that mirrors the state and substance of scientific evidence concerning any one dietary ingredient’s effect on weight would be true. If, for example, the scientific evidence revealed that a dietary substance, e.g., common tea or fiber, reduced desire to consume by creating a feeling of satiety, a carefully crafted representation of the evidence without a specific recitation of unprovable quantums of weight loss achievable would not be inherently misleading. Thus, suppression of the claim based on the notion that a penultimate relationship between ingestion of the substance and pounds lost had not been shown would be unconstitutional, as the Pearson v. Shalala case so amply confirms. Pearson v. Shalala, 164 F.3d 650, 655 (D.C. Cir. 1999); Whitaker v. Thompson, 284 F.Supp.2d 13, 15 (D.D.C. 2002). See also Thompson v. W.States Med. Ctr., 535 U.S. 357 (2002).

Under the four part Central Hudson test it is thus the case that the FDA could not determine presently, without a specific claim before it, that all weight loss claims for a dietary supplement would be false. Each claim’s validity depends on its precise wording and the evolving scientific evidence upon which the claim is based. Consequently, a blanket ban will necessarily result in suppression of non-misleading claims thus making it presumptively unconstitutional. See Thompson v. Western States Med. Ctr., 535 U.S. 357, 377 (2002) (speech ban that presumptively precludes non-misleading speech along with that which is inherently misleading does not survive constitutional scrutiny under the commercial speech test); (44 Liquormart, Inc. v. Rhode Island, 517 U.S. 484, 502 (1996) (“complete speech bans . . . are particularly dangerous because they foreclose alternative means of disseminating certain information”); Zauderer v. Office of Disciplinary Counsel of Supreme Court of Ohio, 471 U.S. 626, 636 (1985) (“The State’s burden is not slight; the free flow of commercial information is valuable enough to justify imposing on would-be regulators the costs of distinguishing the truthful from the false, the helpful from the misleading, the harmless from the harmful”); Ibanez v. Fla. Dep’t of Bus. & Prof’l Regulation, 512 U.S. 136 (1994) (speech ban that encompasses non-misleading statement did not withstand constitutional scrutiny because government unable to establish that ban directly and materially advances substantial state interest); see also Pearson v. Shalala,164 F.3d 650, 655 (D.C. Cir. 1999) (Government may impose a blanket ban on speech that is inherently misleading; but may not do so on speech that is, at worst, only potentially misleading).

Under the third and fourth prongs of the Central Hudson test, the blanket ban also fails to pass constitutional muster. Under the third prong, the ban must be shown to directly advance the government’s interest. Presumably the government’s interest is not the protection of GlaxoSmithKline’s market but reduction of fraud in the market. If the latter, then a blanket ban does not directly advance the government’s interest. In construing the fit between means and ends, the Court has said that it has to be reasonable. Board of Trustees of State Univ. of N.Y., 492 U.S. 469, 476 (1989); Edenfield v. Fane, 507 U.S. 761 (1993). To be reasonable, the fit cannot be overbroad such that non-misleading speech is ensnared with inherently misleading speech, as would be the case here. Id. Thus, the means chosen does not directly advance the anti-fraud end and also renders the ban unconstitutional.

Under the fourth prong of the Central Hudson test, the ban cannot be more extensive than necessary to serve the government’s interest. Thompson v. W. States Med. Ctr., 535 U.S. 357 (2002). In that regard, if there are obvious, less speech restrictive alternatives, they must be used. Rubin v. Coors. Brewing Co., 514 U.S. 476, 491 (1995) (“The [Government’s] defects are further highlighted by the availability of alternatives that would prove less intrusive to the First Amendment’s protections for commercial speech”). The reliance on case by case enforcement against inherently misleading claims, currently the law, is an obvious, less speech restrictive alternative to the blanket ban advocated by GlaxoSmithKline. Moreover, in cases where the precise content of the speech harbors a potential to mislead that may be disabused through reliance on a disclaimer, it is the constitutional duty of the government to rely on a disclaimer in lieu of outright suppression. See Pearson v. Shalala, 164 F.3d 650, 657 (D.C. Cir. 1999); Whitaker v. Thompson, 353 F.3d 947, 953 (D.C. Cir. 2004)

For the foregoing reasons, the blanket ban advocated by SmithKline is prohibited because it results in the censorship of constitutionally protected speech.

GlaxoSmithKline’s Call for Unlawful Agency Action.

Under the Administrative Procedure Act, FDA is prohibited from engaging in an abuse of discretion. GlaxoSmithKline’s request that FDA use its power in complicity with that company to remove all claims from the market that would compete with its weight loss claims for Alli is inherently corrupt (reliance on government processes to achieve a private commercial restraint of trade) and, thus, invites an abuse of discretion. 5 U.S.C. § 706(2)(A); See also Davidson v. United States Dep’t of Energy, 838 F.2d 850 (6th Cir. 1988). The APA also prohibits the adoption of a legislative rule without notice and comment rulemaking. 5 U.S.C. § 553; See Sugar Cane Growers Cooperative v. Veneman, 289 F.3d 89 (D.C. Cir. 2002). In the first instance, in recognition that the rule it adopted defining allowable structure/function claims was legislative, FDA relied upon notice and comment rulemaking. See “Dietary Supplements; Comments on Report of the Commission on Dietary Supplement Labels” 63 Fed. Reg. 23633, 23625 (April 29, 1998). It thus made a preliminary determination that in acting in areas as sensitive as those concerning what information the public may receive (i.e., the health effects of nutrients), it cannot proceed by acting unilaterally but had to proceed through notice and comment rulemaking. Because the rules in question do determine the permissible scope of fundamental rights of all parties who speak in the food and dietary supplement markets, the rules are legislative and do require compliance with the familiar notice and comment requirements of the APA. 5 U.S.C. § 553; Sprint Corporation v. Federal Communications Comm’n, 315 F.3d 369 (D.C. Cir. 2003). GlaxoSmithKline’s demand that FDA proceed unilaterally is, thus, a call for unlawful agency action.

Conclusion.

For the foregoing reasons, the FDA should not act on GlaxoSmithKline’s petition except to deny it. The petition is borne of an undisclosed interest in securing from competition weight loss claims to the market advantage of GlaxoSmithKline’s Alli over-the-counter weight loss drug. If the FDA becomes complicit in that anti-competitive action, it will necessarily abuse its discretion in violation of the Administrative Procedure Act. The petition calls for an unconstitutional blanket speech ban. The petition calls for unilateral action in violation of the Administrative Procedure Act’s prohibition on legislative rulemaking without notice and comment.

Respectfully submitted, 
Jonathan W. Emord 
Andrea G. Ferrenz 
Ryan Kelley 
Counsel to Durk Pearson and Sandy Shaw