Weight Loss Sale

The Durk Pearson & Sandy Shaw®
Life Extension News™

Vol. 7 No. 2 July 2004

"If the law says that . . . a [government] board or authority may do what it pleases, anything that board or authority does is legal—but its actions are certainly not subject to the Rule of Law. By giving the government unlimited powers, the most arbitrary rule can be made legal; and in this way a democracy may set up the most complete despotism imaginable.

The conflict is thus not, as it has often been misconceived in nineteenth-century discussions, one between liberty and law. As John Locke had already made clear, there can be no liberty without law. The conflict is between different kinds of law—law so different that it should hardly be called by the same name: one is the law of the Rule of Law, general principles laid down beforehand, the ‘rules of the game’ which enable individuals to foresee how the coercive apparatus of the state will be used, or what he and his fellow-citizens will be allowed to do, or made to do, in stated circumstances. The other kind of law gives in effect the authority power to do what it thinks fit to do. Thus the Rule of Law could clearly not be preserved in a democracy that undertook to decide every conflict of interests not according to rules previously laid down but ‘on its merits."

— F. A. Hayek, The Road to Serfdom (1944)

Table of Contents This Issue

1. Inflammation After Eating a Mixed Meal: Eating May Be Hazardous to Your Health
2. Prolactin: Sex and Immune Activation
3. Loss of Muscle Mass with Aging: Interleukin-6 and Tumor Necrosis Factor-alpha
4. Lycopene Inhibits Mineral Resorption from Bone
5. Curcumin May Be Effective in Treating Cystic Fibrosis
6. FDA Continues Its Murderous Rampage and Still Violates the First Amendment


Inflammation After Eating a Mixed Meal: Eating May Be Hazardous to Your Health

A new study1 found inflammatory effects in nine normal-weight subjects after eating a 910-calorie mixed meal. The subjects were nondiabetic, aged 29–38 years, and of normal weight. The subjects’ gender(s) was not provided.

The mixed meal consisted of 910 calories from egg-muffin and sausage-muffin sandwiches and two hash-browns, with 81 grams of carbohydrate, 51 grams of fat, and 32 grams of protein, eaten over 15 minutes. The control subjects were given 300 ml of water in a fasted state in place of the mixed meal.

This is a high-carbohydrate, high-fat, and (the way we see it) not very appetizing meal. The purpose of the study, however, was not to test for a good or bad diet but to see whether “. . . the intake of a 900-calorie mixed meal induces an increase in ROS [reactive oxygen species] generation by leukocytes and an inflammatory response at the cellular level.” The results confirmed the hypothesis.

Plasma glucose concentrations were not changed significantly after the meal, but plasma insulin concentrations increased significantly at 1 hour after the meal and remained elevated at 2 and 3 hours. Plasma triacylglycerol (triglycerides) were increased significantly at 2 and 3 hours following the meal. Nuclear NF-kappaB in mononuclear cells was statistically significantly increased after the meal, probably due to the inhibited expression of I-kappaB, the protein that maintains NF-kappaB in the cytosol of cells, preventing it from moving into the nucleus. The I-kappaB expression was decreased by the induction of IKK-alpha and IKK-beta, which phosphorylate I-kappaB and cause its degradation.

C-reactive protein, an inflammatory substance associated with cardiovascular disease risk, was significantly increased after the meal. The authors note that proinflammatory stimuli, such as endotoxin and cytokines (such as tumor necrosis factor-alpha), induce an increase in intranuclear NF-kappaB and a decrease in I-kappaB.

NADPH oxidase is a major source of superoxide radicals; the p47phox subunit of this enzyme in the mononuclear cell homogenates was increased significantly at 1 hour and remained elevated for 3 hours after the meal. All nine subjects showed increased ROS (reactive oxygen species) generation by mononuclear cells after meal intake. None of these proinflammatory changes occurred in the control subjects getting water.

The authors note that these proinflammatory effects last for about 3 hours after the intake of the meal. Since people may eat again only a few hours after a meal, it is possible that chronic overeating may result in a nearly continuous state of inflammation. These effects may explain (at least in part) the reason for the reduced postischemic brachial artery vasodilation after eating a meal (especially a high-fat meal). Earlier studies have shown that taking vitamins E and C before a meal prevents this abnormality. As the authors note, these effects of ordinary eating in nonobese individuals need to be studied further, because obesity is associated with an increase in oxidative stress and an increase in plasma concentrations of proinflammatory mediators, such as tumor necrosis factor-alpha, interleukin-6, and C-reactive protein. It almost (but not quite) makes you wish you didn’t need to eat.

This study underscores the need to take antioxidants just before or with a meal. We hypothesize that a possible explanation for inflammatory reactions after eating food is that for most of human history, the food eaten was much dirtier (contained far more bacteria, parasites, and viruses) than our food today. Thus, having an inflammatory reaction after eating food that would be protective against infection makes sense. Using Third World countries as a model, the likelihood is great that infectious disease will be the #1 killer before you reach reproductive age (except in areas where there is ongoing warfare). The inflammation following food consumption also provides an explanation, at least in part, for why eating less (as in caloric restriction) has healthful benefits.

  1. Aljada et al. Increase in intranuclear nuclear factor kappaB and decrease in inhibitor kappaB in mononuclear cells after a mixed meal: evidence for a proinflammatory effect. Am J Clin Nutr 79:682-90 (2004).

Prolactin: Sex and Immune Activation

The hormone prolactin does a great deal more than just induce lactation in women who are breastfeeding babies. Yet it seems to be somewhat ignored as a major regulator of processes involved in autoimmune diseases and of orgasm and sexual function in both men and women.

The production of orgasm, either by masturbation or coitus, results in a large release of prolactin immediately afterward, which remains elevated for about one hour.1 Sexual arousal alone induces no changes in prolactin in either men or women. Hyperprolactinemia, where prolactin levels are higher than normal, leads to suppression of libido and to sexual dysfunction in both men and women. We interpret this effect of high prolactin levels as similar to the refractory period following sex. Prolactin levels go up after orgasm but then, over about an hour, return to normal. During the postorgasmic period, there are high prolactin levels and loss of libido and sexual function until prolactin levels return to normal. If “normal” levels are already high, however, there may never be an end to the refractory period.

A commonly used dopaminergic agonist (treatment for Parkinson’s disease), bromocriptine (Parlodel®), is very effective in normalizing hyperprolactinemia. We have been using it for over 25 years as an anti-aging drug because keeping prolactin levels down is also known to maintain the sensitivity of the tuberoinfundibular dopamine neurons, the brain area that responds to prolactin.1 Another drug, carbergoline, is also available for normalizing hyperprolactinemia. However, we like bromocriptine because it has been used for a very long time by many millions of people, and any possible negative effects would have long since shown up.

One unfortunate effect of the SSRI (selective serotonin receptor inhibitor) antidepressant drugs is that they are considered to be “. . . the primary producer of drug-induced hyperprolactinemia, although no research has accurately described the prevalence of this phenomenon.”2 Another study3 found that oral administration of 200 mg of 5-hydroxytryptophan (5-HTP) in 18 of 21 normal subjects significantly increased plasma prolactin levels.

Excess amounts of prolactin could also be a hazard because prolactin is known to play a major role in the growth of certain tissues (breast, prostate4).

Prolactin plays a role in autoimmune diseases by stimulating autoimmune B cells. For example, systemic lupus erythematosus (SLE) can be a very severe, even fatal, autoimmune disease with autoreactive B cells attacking every organ in the body, DNA, etc. Small-scale trials with SLE patients being treated with bromocriptine have suggested a beneficial effect in mild and moderate disease activity. Recent studies in female NZB/WF1 lupus-prone mice demonstrated that hyperprolactinemia accelerated disease and decreased survival, while bromocriptine increased survival.5 Scientists have found that estradiol blocks the deletion of naive autoreactive B cells that arise in the bone marrow. Estrogen increases prolactin secretion, and B cells express prolactin receptors.5 Another paper6 reports that the inflammatory cytokine IL-6 gene expression is high in lupus and that IL-6 has been reported to stimulate prolactin release from cultured rat pituitary cells.

Besides bromocriptine, it has been reported that cholinergic stimulation by systemic or intracerebroventricular (professional driver—closed course—don’t try this at home) administration causes a decrease in serum prolactin concentration.7 Other studies have found cholinergic drugs to inhibit prolactin secretion and tumor necrosis factor.8,9 Increased cholinergic neuronal activity can be achieved by taking supplemental choline and vitamin B5, acetylcholinesterase inhibitors (such as galantamine), and N-acetylcarnitine. Prolactin increases with age; much of this may be due to the damage that takes place in the dopaminergic and cholinergic nervous systems, which suppress prolactin release. In one study, researchers found that, in healthy subjects between the ages of 60 and 85 years (as compared to healthy individuals between the ages of 20 and 40 years), only 16% of ingested choline was taken up by the brain through the blood-brain barrier, even though there was a similar increase in plasma choline concentration in both younger and older subjects.10

Also, another reason to get rid of excess fat is that adipocytes (fat cells) release leptin, a hormone that can exert a stimulatory effect on steroid-induced or spontaneous prolactin.7

References

  1. MohanKumar et al. Effects of chronic bromocriptine treatment on tyrosine hydroxylase (TH) mRNA expression, TH activity, and median eminence dopamine concentrations in ageing rats. J Neuroendocrinol 13:261-9 (2001).
  2. Kruger et al. Orgasm-induced prolactin secretion: feedback control of sexual drive? Neurosci Biobehav Rev 26:31-44 (2002).
  3. Kato et al. Effect of 5-hydroxytryptophan (5-HTP) on plasma prolactin levels in man. J Clin Endocrinol Metab 38:695-7 (1974).
  4. Wennbo et al. Transgenic mice overexpressing the prolactin gene develop dramatic enlargement of the prostate gland. Endocrinol 138:4410-15 (1997).
  5. Peeva et al. Bromocriptine restores tolerance in estrogen-treated mice. J Clin Invest 106(11):1373-9 (2000).
  6. Walker et al. Prolactin and autoimmune disease. Trends Endocrinol Metab 4:147-151 (1993).
  7. Freeman et al. Prolactin: structure, function, and regulation of secretion. Physiol Rev 80(4):1523-1631 (2000).
  8. Grandison et al. Inhibition of prolactin secretion by cholinergic drugs. Proc Soc Exp Biol Med 145:1236-9 (1974).
  9. Wang et al. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 421:384-8 (2003).
  10. Cohen et al. Decreased brain choline uptake in older adults. JAMA 274(11):902-7 (1995).

Loss of Muscle Mass with Aging: Interleukin-6 and Tumor Necrosis Factor-alpha

A recent study1 reports that, in healthy elderly men and women, higher plasma concentrations of the inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were associated with lower muscle mass and lower muscle strength. The authors used baseline data (1997–1998) of the Health, Aging, and Body Composition (Health ABC) Study, which included 3075 black and white men and women aged 70–79 years. With the exception of white men, elderly persons with high levels of IL-6 (more than 1.80 pg/ml) as well as high levels of TNF-alpha (more than 3.20 pg/ml) had smaller muscle area, less appendicular muscle mass (arms and legs), lower knee extensor strength, and lower grip strength. Blacks, who had higher IL-6 and lower TNF-alpha than whites, had greater muscle area and strength compared to whites in both men and women.1

IL-6 and TNF-alpha are proinflammatory cytokines, chemical signals sent and received by the immune system. While cytokines play important roles in initiating and regulating inflammatory processes that protect against infections and induce repair at sites of injury, overproduction of inflammatory cytokines or failure to discontinue inflammation can cause a wide variety of disease conditions, such as arthritis, multiple sclerosis, inflammatory bowel disease, atherosclerosis, cancer, the wasting due to cancer (cachexia), and (as mentioned above) the loss of muscle mass with aging. Chronic administration of TNF-alpha or another cytokine, IL-1, induced weight loss and skeletal muscle wasting in rats.2

Another paper2 reports on a possible mechanism for the muscle wasting with aging reported above. In cell culture and in male C57/bl6 mice, TNF-alpha was shown to inhibit myogenic differentiation by destabilizing the MyoD protein [which plays an important role in cell-cycle exit of differentiating myoblasts (developing muscle cells), muscle-specific gene expression, and myotube (structural elements of muscle cells) formation]. These effects were mediated by NF-kappaB activation, as is seen with oxidative stress and inflammation. Another paper3 reported that transient (as little as 10 minutes) exposure of human myoblasts to TNF-alpha inhibited serum and insulin-like growth factor-1-stimulated protein synthesis. The authors note that the decrease in protein synthesis they observed was similar to the inhibition of protein synthesis seen in skeletal muscle from septic animals.

In a dramatic demonstration of the protective effect of blocking excess TNF-alpha activity in a disease characterized by massive skeletal muscle loss, the anti-TNF-alpha drug Remicade® has been shown to protect dystrophic skeletal muscle from necrosis.4 (The myopathy of Duchenne’s muscular dystrophy is caused by defects in a cell-membrane-associated protein, dystrophin. However, in this study, the blocking of TNF-alpha in a mouse model of the disease showed marked protection against skeletal muscle breakdown, even though it did nothing to correct the dystrophin defects.)

There are many substances that have been reported to reduce inflammation and TNF-alpha levels, including regular exercise,5 acetylcholinesterase inhibitors (in Alzheimer’s disease patients),6 alpha-lipoic acid,7 quercetin,8 N-acetylcysteine,9 nonsteroidal anti-inflammatory drugs,10 estrogen,11,12 and antioxidant vitamins.13 Getting rid of excess fat is also a useful way of reducing TNF-alpha levels, since adipocytes (fat cells) release large amounts of the cytokine.

References

  1. Visser et al. Relationship of interleukin-6 and tumor necrosis factor-alpha with muscle mass and muscle strength in elderly men and women. J Gerontol 57A(5):M326-32 (2002).
  2. Langden et al. Tumor necrosis factor-alpha inhibits myogenic differentiation through MyoD protein destabilization. FASEB J 18:227-36 (2004).
  3. Frost et al. Transient exposure of human myoblasts to tumor necrosis factor-alpha inhibits serum and insulin-like growth factor-1 stimulated protein synthesis. Endocrinol 138(10):4153-9 (1997).
  4. Grounds and Torrisi. Anti-TNF-alpha (Remicade®) therapy protects dystrophic skeletal muscle from necrosis. FASEB J 18:676-82 (2004).
  5. Greiwe et al. Resistance exercise decreases skeletal muscle tumor necrosis factor-alpha in frail elderly humans. FASEB J 15:475-82 (2001).
  6. Lugaresi et al. IL-4 in vitro production is upregulated in Alzheimer’s disease patients treated with acetylcholinesterase inhibitors. Exp Gerontol 39:653-7 (2004). [This paper reports that, in AD patients treated with acetylcholinesterase inhibitors (as compared to untreated AD patients), there was a much higher level of IL-4 (five times higher in unstimulated cultures of peripheral blood mononuclear cells). IL-4 (interleukin-4) is an immunosuppressive cytokine; evidence suggests that it prevents neuronal cell injury. The mechanism may be IL-4 inhibition of interferon gamma and the consequent decrease in the concentration of TNF-alpha and nitric oxide.]
  7. Zhang and 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).
  8. Wang and 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).
  9. Victor et al. N-Acetylcysteine protects mice from lethal endotoxemia by regulating the redox state of immune cells. Free Rad Res 37(9):919-29 (2003).
  10. Joussen et al. Nonsteroidal anti-inflammatory drugs prevent early diabetic retinopathy via TNF-alpha suppression. FASEB J (Jan. 30, 2002).
  11. Cenci et al. Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-alpha. J Clin Invest 106(10):1229-37 (2000).
  12. 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).
  13. Vassilakopoulos et al. Antioxidants attenuate the plasma cytokine response to exercise in [untrained] humans. J Appl Physiol 94(3):1025-32 (2003).

Lycopene Inhibits Mineral Resorption from Bone

In a cell-culture study (cells from rat bone marrow),1 lycopene (water-dispersible microemulsion preparation) was shown to inhibit basal and parathyroid hormone-stimulated osteoclast mineral resorption (as occurs in bone loss) and also to inhibit the production of reactive oxygen species (thought to be involved in bone loss) produced by osteoclasts. The authors also found that lycopene was not cytotoxic to the osteoclasts, but merely inhibited development. They concluded that these findings “. . . are novel and may be important in the pathogenesis, treatment, and prevention of osteoporosis.”

Reference

  1. Leticia et al. Lycopene I—effect on osteoclasts: lycopene inhibits basal and parathyroid hormone-stimulated osteoclast formation and mineral resorption mediated by reactive oxygen species in rat bone marrow cultures. J Medicinal Food 6(2):69-78 (2003).

Curcumin May Be Effective in Treating Cystic Fibrosis

The curcumin literature continues to expand, with reports of this major constituent of the spice turmeric being extended to other diseases and medical conditions. In the latest such report,1 curcumin is reported to correct cystic fibrosis defects in a gene-targeted homozygous mouse model of the disease. The mice carried two copies of the human gene for the deltaF508 CFTR (cystic fibrosis transmembrane conductance regulator) protein. This mutation in humans is responsible for about 69% of cases, with 90% of cystic fibrosis patients carrying at lease one copy of the gene. The normal protein functions as a chloride channel on the cellular surface, whereas the mutated gene results in an improperly folded protein that is destroyed by the proteosome (cellular garbage disposal) instead of being delivered to the cell surface.

The authors report that the mice were given 45 mg of curcumin per kilogram of body weight orally daily for 3 days. This dose was chosen because, on a weight per weight basis, it is similar to doses that have been well tolerated by humans in previous studies. In the curcumin-treated mice, the deltaF508 CFTR protein was delivered to the cell surface, the functional localization, instead of being destroyed by the proteosome. Mice were also tested for other effects: for example, homozygous mice with the genetic defect are very susceptible to gastrointestinal obstruction, resulting in considerable mortality. Six of 10 untreated mice died, whereas only one mouse treated with curcumin (or the osmotic laxative Colyte) died.

The authors suggest that “. . . curcumin and curcumin derivatives represent promising new candidate compounds that may prove useful in the search for small-molecule pharmacotherapies for cystic fibrosis and for other protein-folding diseases.” (Emphasis added.)

Reference

  1. Egan et al. Curcumin, a major constituent of turmeric, corrects cystic fibrosis defects. Science 304:600-2 (2004).

FDA Continues Its Murderous Rampage and Still Violates the First Amendment

Whitaker v. Thompson, in which we are coplaintiffs, is still ongoing. In it we argue that FDA suppression of a truthful, nonmisleading claim that 320 mg of saw palmetto per day can reduce the symptoms of benign prostatic hypertrophy (BPH) is a violation of the First Amendment. The FDA argues that this is a “drug” claim, since it concerns treatment, a category of speech that they wish to restrict to just OTC and prescription pharmaceuticals. Of course, the First Amendment allows no such restriction of certain speech to just particular speakers of the government’s choosing. However, Whitaker v. Thompson lost in the court of appeals (which was expected), and we have appealed to the U.S. Supreme Court. If the Supremes won’t take the case (expected), we have another strategy, which we will tell you about as soon as we start doing it.

Proscar® (finasteride), an FDA-approved treatment for BPH, has now been reported to increase (possibly by 200 times) the risk of breast cancer in men. This is normally a very rare disease. A letter1 in the Feb. 18, 2004 Journal of the National Cancer Institute reports that “Proscar shrinks androgen-dependent prostate tissue by inhibiting steroid 5-alpha-reductase, an enzyme that converts testosterone to dihydrotestosterone. However, inhibition of DHT production alters the estrogen-to-androgen ratio and may also increase the risk of gynecomastia [breast enlargement] and male breast cancer. Reports to the U.S. Food and Drug Administration (FDA) from June 1992 through February 1995 showed that gynecomastia had been observed in 214 men receiving Proscar therapy. Two of these men were subsequently found to have invasive ductal breast carcinoma. There was also a higher incidence of gynecomastia in men participating in the Prostate Cancer Prevention Trial. The rate of gynecomastia was 426 (4.5%) of 9423 subjects randomly assigned to the Proscar arm, compared with 261 (2.8%) of 9457 subjects randomly assigned to the placebo arm. There was one case of breast cancer in each arm of the trial.

“Evidence of the association of Proscar with male breast cancer comes from the Medical Therapy of Prostatic Symptoms (MTOPS) study, a National Institutes of Health (NIH)-sponsored study of about 3047 men that compared Proscar, doxazosin, and the combination for the treatment of BPH. . . . According to a letter from the NIH to the MTOPS principal investigators, one man in the Proscar/doxazosin group and three in the Proscar-alone group developed male breast cancer. The rate of breast cancer in this trial for men taking Proscar either alone or with doxazosin was therefore 4 in 1554, or nearly 200 times that of the general population.”

It is also noteworthy that the FDA has approved the use of finasteride (under the name Propecia®), at half the dose for treating BPH, for treating male-pattern baldness!

The authors of the above letter strongly recommend that the FDA include this information in the manufacturer’s patient information leaflet for Proscar and in its advertisements. To our knowledge, this has not been done.

A major active ingredient in the herb saw palmetto is beta-sitosterol, which is found in large quantities in soy products. Epidemiological studies in people and countries where they consume large amounts of soy products show a lower incidence of both breast cancer and prostate cancer. Saw palmetto has been used for perhaps thousands of years as a food. There is no evidence that it increases the incidence of either gynecomastia or breast cancer.

Unfortunately, the FDA is in bed with the pharmaceutical companies, and vice versa. Pharmaceutical companies have been corrupted by being able to use the guns of the FDA to stave off possible competitors, such as dietary supplement saw palmetto. Likewise, the FDA has been corrupted by being able to use pharmaceutical companies as sources of money (hundreds of millions per year) and power. This sort of two-way corruption is typical of all the regulatory agencies and was, in fact, first noted by the Marxist economist Gabriel Kolko at the turn of the twentieth century (who proposed the “capture” theory of regulatory agencies, where the very industry intended to be regulated took over the agency). To support their client companies, the FDA is suppressing free speech so that manufacturers and vendors of competitive products (such as saw palmetto) cannot market them to consumers by truthfully telling what they can do. The FDA is also willing to overlook drug risks, such as what appears to be a 200-times increased risk of breast cancer in men using Proscar, a billion-dollar-plus per year drug, at the same time that they are attacking dietary supplements containing ephedrine alkaloids, which pose much less risk.

The sad ending to this story will be a tidal wave of class action lawsuits against the company manufacturing Proscar by men who develop breast cancer as a result of taking it, and it will be the pharmaceutical company, not the FDA, that will have to pay all of these costs. In the meantime, those of us who desire freedom of informed choice will have to fight on as best we can. As most of the FDA’s power comes from suppression of information, the First Amendment is our best ally in this battle.

Reference

  1. Lee and Ellis. Male breast cancer during finasteride therapy. J Natl Cancer Inst 96(4):338 (2004).

© 2005 by Durk Pearson & Sandy Shaw