November 2000 Blog with Durk and Sandy

If you love wealth greater than liberty, the tranquility of servitude greater than the animating contest for freedom, go home from us in peace. We seek not your counsel, nor your arms. Crouch down and lick the hand that feeds you. May your chains set lightly upon you, and may posterity forget that ye were our countrymen.
– Samuel Adams, American Revolutionary

He has erected a multitude of New Offices, and sent hither swarms of Officers to harass our people, and eat out their substance.
– The Declaration of Independence

HOMOCYSTEINE ACCELERATES CELL SENESCENCE AND SHORTENS TELOMERES

Researchers set up an endothelial-cell-culture test system to examine the effects of homocysteine on cell senescence. Their remarkable findings included the revelation that homocysteine increased the amount of telomere length lost per population doubling (a nearly threefold increase in telomere shortening), an effect that was inhibited by the peroxide scavenger catalase. Chronic exposure of the endothelial cells to homocysteine also increased the expression of two cell-surface molecules involved in vascular disease and cancer, ICAM-l (intracellular adhesion molecule-l) and PAI-1 (plasminogen activator inhibitor-1). The level of ICAM-1 and PAI-1 correlates with the degree of endothelial senescence. The authors concluded that homocysteine accelerates the rate of cellular senescence via an oxidation/reduction-dependent pathway.¹

Many of the atherogenic effects of homocysteine have been ascribed to its ability to increase hydrogen peroxide generation.¹ And, as we have reported earlier, hydrogen peroxide is also known to increase insulin resistance,² another major source of aging damage.

As the authors note, the fact that homocysteine increased the loss of telomere length with each population doubling shows that telomere length is not determined merely by the number of doublings but, as found here, can be affected by oxidation state. If so, this shows that the free radical theory of aging and the telomere theory of aging are not necessarily separate mechanisms.

Finally, previous studies done by others reported that genomic DNA isolated from areas in human blood vessels prone to atherosclerosis had shorter telomere length when compared to adjacent nondiseased areas.

Homocysteine is recognized by nearly everyone other than the FDA as an independent risk factor for atherosclerosis, though large, randomized studies determining how much homocysteine reductions of various amounts may reduce cardiovascular disease outcomes have yet to be done. Such studies probably never will be done, because vitamins cannot be patented, hence, there will be no way for the many millions of dollars invested in such expensive studies to be recovered. The level of evidence for cardiovascular protection by reducing homocysteine levels is at least as strong as that of the cardiovascular protective effects of soy and plant stanols and sterols; these are now FDA-approved claims for foods. Although supplements of folic acid and vitamins B6and B12 can lower homocysteine levels in both animals and humans, the FDA persists in violating the free speech rights of supplement producers and consumers guaranteed by the First Amendment by prohibiting a truthful health claim that folic acid and vitamins B6and B12 may reduce the risk of cardiovascular disease. We have sued to force the agency to issue the approval. See www.emord.com for the latest on the suit and on how you can help.

References

1. Xu et al., “Homocysteine Accelerates Endothelial Cell Senescence,” FEBS Letters 470:20-24 (2000).
2. Hansen et al., “Insulin Signaling Is Inhibited by Micromolar Concentration of Hydrogen Peroxide,” J. Biol. Chem. 274(35):25078-25084 (1999).

WHY PRESCRIPTION DRUGS ARE SO EXPENSIVE, AND WHAT TO DO ABOUT IT

We can think of four main reasons that prescription drugs are expensive:

1. The FDA. The agency prevents competition between prescription drugs and less expensive dietary supplements that may be able to provide similar benefits with lower risks of adverse effects and side effects – for example, finasteride vs. saw palmetto to treat benign prostatic hypertrophy. The FDA blocks competition by refusing to approve health claims for dietary supplements and fighting the free speech rights (to provide truthful health information) of dietary supplement companies to inform consumers who use supplements and want such information.

We (along with the American Preventive Medical Association, which joined us as coplaintiff and helped pay the legal bills) won a landmark court decision in Pearson vs. Shalala (U.S. Court of Appeals for the District of Columbia Circuit, 15 January 1999). The court ruled that the FDA’s prohibition of truthful, nonmisleading health claims for dietary supplements was unconstitutional and that, even if the level of scientific support for a claim did not meet an FDA-defined standard, the agency would have to approve the claim and provide a disclaimer that would prevent any potential to mislead the public. After spending some $200,000 to get that great win, the FDA has openly refused to comply with the court’s ruling, continuing to suppress the four truthful claims at issue (as well as many others). The money wasn’t wasted, however, as we continue to pursue the FDA with further legal action intended to bring the agency to heel. See www.emord.com for all the action, including briefs and oral arguments, court decisions, etc. And if the FDA’s arrogant actions infuriate you as much as they do us, please consider sending a donation to support the case. Make your check out to the Pearson & Shaw Litigation Fund and send to Emord & Associates, 5282 Lyngate Court, Burke, VA 22015. Thanks!

2. The FDA. The agency disallows the importation of FDA-approved prescription drugs manufactured by FDA-approved facilities in other countries, except by the drug manufacturers. Recent bills by Congress may order the FDA to discontinue that practice, although (as we have seen in the FDA’s abrogation of free speech rights in the case of dietary supplement health claims) they may simply refuse to obey Congress. It is up to Congress to punish the FDA for failing to obey congressional statute, such as by reducing the FDA’s budget. (If the Democrats retake the House in the upcoming election, the FDA will not have to worry about congressional oversight, since the House’s #1 FDA ally and pharmaceutical industry shakedown artist, Henry Waxman, would then be back in power.)

3. The FDA. The cost of getting approval for a single new drug entity has now reached about $500,000,000. Only large pharmaceutical companies can afford to spend that sort of money, even with a period of market monopolization through patents within which to recover their money and get a reasonable return on their investment. Approval costs are far higher here than in other advanced countries. Getting approval costs down by, for example, reducing the FDA’s authority to overseeing just safety, rather than overseeing both safety and efficacy, is one way to dramatically reduce drug costs, as well as to increase our access to many useful treatments that otherwise never reach the market due to these high costs. Let freely interacting scientists, doctors, and patients determine relative efficacy in the only way that it matters – in competition with other treatments of individual patients, whose response to a drug may vary widely.

4. The FDA. The system of patented protection of pharmaceutical drugs now includes dangerous provisions whereby the FDA can, for whatever reason it likes (though supposedly to make up for FDA delays in approval), extend (or not) the patent rights on prescription drugs by six months to three years. This has greatly expanded its power (because, for popular drugs, we are talking about billions of dollars in monopoly market rents each year) and fosters the corruption of FDA officials by creating a bribery incentive for pharmaceutical companies to try to get those extended patents and for generic drug companies to try to get the FDA not to grant them. Right now, for example, there is a battle over the right to offer generic versions of the very expensive Prozac^®(fluoxetine), the patent for which is set to expire in February 2001. The patent may be extended by the FDA for another six months, which would mean another billion or so dollars for its manufacturer. All the manufacturer had to do was to apply for a patent specifying a slightly different dose. Then it simply backs the FDA’s agenda in Congress and pays “user fees.”

The solution to these problems is, in principle, simple: get the FDA out of the drug business. The political problem of getting this done is unfortunately not so simple and is far from cheap. The $100 billion per year in prescription drug sales provides plenty of resources for paying protection money – oops, we mean, “campaign contributions” and “user fees.”

SUPPRESSION OF MELATONIN RELEASE BY DIM LIGHT

There has been growing interest in the many reported health-promoting effects of melatonin, which is released by the pineal gland in mammals during the dark (night) part of the circadian cycle. For example, tumor linoleic acid uptake and metabolism, and the growth that results from it, are suppressed by melatonin. Exposure to constant light increases the incidence of chemically induced mammary cancers, an effect that is presumed to be a result of suppression of melatonin production.

A fascinating new study shows that, at least in rats and, in earlier studies, hamsters, it takes very little light at night to suppress melatonin production and release and alter normal circadian rhythms.¹ A recent hypothesis suggests that the melatonin-suppressive effects of light at night in human populations may contribute to an increased risk of breast cancer. If humans are as sensitive as the Buffalo rats in the new study, then it doesn’t take much light to shut down melatonin production.

The male Buffalo rats were followed under three conditions: 1. Group L:D was exposed to 12 hours each of bright light (300 lux) and complete darkness. One lux is the amount of light from a regular candle at 1 meter. 2. Group L:DL was exposed to 12 hours of bright light (300 lux) followed by 12 hours of dim light (0.25 lux, which is the amount of light from a regular candle at 2 meters, or the light from the full moon). 3. Group L:L was maintained in a constant light environment at 300 lux. The animal quarters were absolutely light-tight, ensuring that no leak of light from outside would affect the results.

The rats were implanted with hepatoma 7288CTC cancer tissue and, under the experimental light conditions described, were followed and evaluated (unblinded) for a latency-to-onset of tumor growth to reach approximately the size of a pea. Tumor weights were estimated through the skin. The latency-to-onset was 10.3 ± 1.0 and 5.0 days for the L:DL and L:L groups, respectively, compared with 16.7 ± 2.3 days for the L:D group. Hence, hepatoma growth rates were two to three times greater in the L:DL and L:L groups, respectively, compared to the L:D controls.

In animals under the L:D cycle, a threefold increase in plasma melatonin levels occurred during the dark phase, whereas no nocturnal increase in plasma melatonin was evident in either the L:L or L:DL groups. In this experiment, exposure to dim light during the dark phase was as effective in suppressing the nocturnal melatonin surge as was constant light. The normal circadian rhythm of food intake was preserved in the L:DL group, however. The animals exposed to constant light consumed food throughout the 24-hour day and showed no diurnal variation in plasma lipid levels. Total food consumption was the same in all three groups, so the differences in tumor growth rate were not caused by differences in linoleic acid availability.

In conclusion, dim light at night was very effective in rats in suppressing melatonin production and release. If humans are similarly sensitive to dim light, this could have significant health consequences.

Reference

1. Dauchy et al., “Dim Light During Darkness Stimulates Tumor Progression by Enhancing Tumor Fatty Acid Uptake and Metabolism,” Cancer Letters 144:131-136 (1999).

LIPOFUSCIN ISN’T INERT GUNK – IT SPEEDS UP AGING OF CELLS IN WHICH IT IS FOUND

Lipofuscin and ceroid are fluorescent pigments of aggregated polymers derived from oxidation products of proteins and lipids, cross-linked by covalent and hydrophobic bonds. They accumulate with age in most postmitotic (nondividing) cells, such as neurons. It has been reported that lipofuscin/ceroid accumulation within aging cells is correlated with aging rate in several mammalian species, despite widely differing aging rates.¹ This correlation doesn’t tell you, though, whether the age pigments are an effect of aging, a cause, or both.

Lipofuscin and ceroid accumulation can be accelerated by increased oxygen stress and by inhibition of lysosomal proteases and lipases, which are processes that accelerate aging in general. Hence, these pigments are considered good markers of aging. What they do to cells in which they accumulate has long been unclear. A new study¹ now reports that lipofuscin/ceroid accumulation decreases proteolysis in cells, decreasing protein degradation and causing an accumulation of oxidized cell proteins.

The lipofuscin/ceroid was found to directly inhibit the activity of proteasomes, cell structures that are supposed to degrade damaged proteins. The test system was comprised of human lung fibroblast cell cultures loaded with artificial lipofuscin or ceroid pigment under conditions of normobaric hyperoxia (40% oxygen at normal atmospheric pressure). The normobaric hyperoxia caused an irreversible senescence-like growth arrest after about 4 weeks and shortened postmitotic life span from 1 1/2 years down to 3 months. By 12 weeks and thereafter, overall proteolysis was significantly depressed. Hyperoxia also caused a “remarkable” increase in lipofuscin/ceroid formation and accumulation over 12 weeks. To test whether the relation between the exposure to lipofuscin/ceroid and decreased proteolysis was causal, lipofuscin/ceroid-loaded cells were next exposed to normoxic conditions. These cells exhibited a gradual decrease in overall protein degradation over 4 weeks of treatment, whereas protein synthesis was unaffected. Proteasome-specific activity decreased by 25% over this period. Incubating purified proteasome with lipofuscin/ceroid preparation showed that the latter directly inhibited proteasomes.

This study supports the hypothesis that the accumulation of heavily damaged, oxidized, and aggregated proteins during postmitotic aging may diminish the effectiveness of proteolytic enzymes and thus accelerate aging. The study also, of course, supports the free radical theory of aging.

Reference

1. Sitte et al., “Proteasome Inhibition by Lipofuscin/Ceroid During Postmitotic Aging of Fibroblasts,” FASEB J. 14:1490-1498 (2000).

NOW WE KNOW HOW SPERM DO IT

A new report on how sperm fertilize eggs has been published.¹ The authors show that nitric oxide synthase is present at high concentrations and is active in sperm after activation of eggs by the acrosome reaction. In this reaction, there is an increase in nitrosation within eggs in seconds after insemination, and this is followed by a calcium pulse of fertilization. Microinjection of nitric oxide (NO) donors or recombinant nitric oxide synthase duplicates these events of egg activation, whereas prior injection of oxyhemoglobin, a physiological scavenger of nitric oxide, prevents egg activation.

It is interesting to note that arginine has been used to promote fertility in bulls, by increasing numbers and motility of sperm, for close to 50 years.

Reference

1. Kuo et al., “NO Is Necessary and Sufficient for Egg Activation at Fertilization,” Nature 406:633-636 (2000).

WHY THE BRITISH NATIONAL HEALTH SERVICE IS HAZARDOUS TO THE HEALTH OF THE BRITISH

An article in the September 6, 2000 Journal of the National Cancer Institute reveals even more bad news about the British National Health service and why the United States should not emulate it. All quotes below are from the article.

According to the article, the British Association of Cancer United Patients (BACUP) has just celebrated its fifteenth birthday; this organization is said (but we don’t know by whom) to have done more than any other single organization to promote patient empowerment in Britain. British patients “used to be treated like children who were ‘seen and not heard.’ They were denied clinical information as a matter of official policy; hospital notes were stamped ‘Not to be seen by the patient.’ Pharmacists were instructed not to tell patients what drugs they had been prescribed.” (D & S comment: Amazing, isn’t it, that British patients are such sheep that they have been willing to take their prescribed little white pills when they didn’t even know what was in them?)

Because of CancerBACUP and others, “old-style British paternalism is now being phased out in Britain in the name of new-style American consumerism and political correctness. New models are emerging – the ‘informed patient,’ the ‘expert patient,’ and the ‘doctor-patient partnership.'”

“The information available from treatment trials from Physician Data Query has been available for some time in the United States, whereas even now they’re not available on a wide-scale basis in the United Kingdom,” said Jean Mossman, chief executive of CancerBACUP. (D & S comment: Of course not. When the government is paying for your therapy, they sure don’t want you to know about all the options. The demand for “free” health care is always much greater than the supply.)

“UK health economists have taken up this theme in the British Medical Journal, arguing that although it may be popular and politically correct to involve the public in health care priority setting, it may not necessarily be a good thing to involve it in rationing decisions.” (!) (D & S comment: In Britain, elite committees, not the public, decide who will and who will not receive lifesaving treatment. Of course they do not want the public to be involved in rationing decisions, since very few members of the public would want to give up their own potentially lifesaving treatment, no matter how costly.)

“By taking the health care purchasing decisions away from the consumer, the [British] National Health Service improves efficiency by allowing only those people with sufficient knowledge of health care to purchase effective medicine on behalf of patients.” (D & S comment: Right, and by keeping patients out of the process, you can ensure that decisions are made impersonally and efficiently on who will live and who will die. Only the market can provide diverse medical services to a population that doesn’t want or need the same one-size-fits-all government choice of treatment.)

Offering “free” health care (whether it is “free” prescription drugs or whatever) always increases the demand for that health care. Hence, you always get rationing of the “free” stuff. Worse yet, the government doesn’t want those who are getting health care through its program to realize they are getting second-class medicine and will usually put provisions into its programs that prevent people “covered” by the program from buying the medicine they want with their own money, just as occurs in the U.S.’s Medicare today.

NEW FINDINGS ON OBESITY

Leptin Regulates Bone Mass 
New reports on metabolic correlates with adiposity (body fat) are pouring into the peer-reviewed literature. Recently it has been reported that the hormone leptin (released largely by fat cells) inhibits bone formation^1,2 and that obesity is associated with high bone mass, apparently because of leptin resistance (insensitivity to leptin) in the most common form of obesity. High bone mass may be the only important health benefit of being fat.

Regulation of Adiposity by Dietary Calcium 
The relationship of greater bone mass and obesity appears to be linked – because calcium is a major regulator of bone formation – to the findings of a new paper³ that reports evidence that dietary calcium has a regulatory effect on body fat. Increasing adipocyte (fat cell) intracellular Ca²⁺ results in a coordinated stimulation of lipogenesis and inhibition of lipolysis. The researchers first became interested in this potential relationship when they found that obese African-Americans, during the course of an unrelated clinical trial on the antihypertensive effect of calcium, lost 4.9 kg in body fat over the course of a year after their calcium intake was increased from about 400 to 1000 mg/day. Although the scientists could not understand this result at the time, they later found that increases in circulating calcitrophic hormones [1,25-(OH)2-D and/or parathyroid hormone] secondary to low-calcium diets stimulate adipocyte Ca²⁺ influx and thereby increase lipid storage.

The hypothesis was further tested by the same researchers using epidemiological data from the NHANES III nutritional survey of Americans. After controlling for energy intake, the relative risk of being in the highest quartile of body fat was set to 1.00 for the lowest quartile of calcium intake and was reduced to 0.75, 0.40, and 0.16 for the second, third, and fourth quartiles, respectively, of calcium intake for women; a similar inverse relationship was also found for men.

These researchers had previously shown that agouti, an obesity gene expressed in human adipocytes, stimulates Ca²⁺ influx and promotes energy storage in human adipocytes by stimulating the expression and activity of fatty acid synthase. Correcting elevations in intracellular Ca²⁺ in adipocytes of transgenic mice overexpressing agoutiwith a Ca²⁺ channel antagonist (nifedipine) for four weeks resulted in clinical improvements in blood pressure, insulin resistance, platelet aggregation, and left ventricular hypertrophy, as well as decreasing adipocyte lipogenesis (synthesis of lipids) and adipose tissue mass.

Moreover, the researchers noted that they found that dairy calcium exerted a greater effect on attenuating fat deposition than a comparable quantity of mineral calcium. A recent randomized clinical trial found a markedly greater weight loss (7.0 vs. 1.7 kg) in patients maintained on a milk-based diet for 16 weeks vs. those maintained on a conventional hypocaloric diet at the same level of energy intake (though, of course, the form of calcium was not the only variable, since there is much more than just calcium in milk).

In a separate study,⁴ different researchers found that, in 56 young Caucasian women 16-31 years of age, calcium intake, corrected by total energy intake, significantly predicted change in body weight and body fat. Subjects with high calcium intake, corrected by total energy intake, gained less weight and body fat. Dietary intake was assessed by 3-day diet records.

WARNING: Do not take megadoses of calcium in an attempt to lose fat. Excess calcium can cause kidney damage, calcium stones, and bone spurs. In the case of calcium, RDA levels are reasonable. It is known, however, that the calcium found in dairy products is more bioavailable than other forms of calcium.

Decreased Availability of Vitamin D in Obesity 
The increased bone mass associated with obesity is surprising in light of the findings of another new study:⁵ that vitamin D is less available in the obese, which results in both vitamin D insufficiency and secondary hyperparathyroidism.

References

1. Ducy et al., “Leptin Inhibits Bone Formation through a Hypothalamic Relay: A Central Control of Bone Mass,” Cell 100:197-207 (2000).
2. Fleet, “Leptin and Bone: Does the Brain Control Bone Biology?” Nutrition Reviews 58(7):209-211 (2000).
3. Zemel et al., “Regulation of Adiposity by Dietary Calcium,” FASEB J. 14:1132-1138 (2000).
4. Teegarden, Lin, Weaver, Lyle, McCabe, “Calcium Intake Relates to Change in Body Weight in Young Women,” FASEB J. 13(5) Abstracts, Experimental Biology 99, Washington, DC, April 17-21, 1999.
5. Wortsman et al., “Decreased Bioavailability of Vitamin D in Obesity,” Am. J. Clin. Nutr. 72:690-693 (2000).

SEROTONERGIC NERVOUS SYSTEM AND INSULIN SENSITIVITY

A new paper¹ reports a close relationship between central serotonin (5-HT) activity and insulin sensitivity in healthy young male volunteers.

The researchers set up this experiment on the basis of earlier data suggesting such a relationship, such as the findings that depressed patients have higher glucose and insulin levels in the glucose tolerance test as compared to nondepressed patients. In other studies, depressed patients have shown a decreased hypoglycemic response to insulin (decreased insulin sensitivity). Moreover, substances that increase central serotonin activity, such as the 5-HT agonist D-fenfluramine or the selective serotonin reuptake inhibitor fluoxetine (Prozac^®) have been reported to increase peripheral sensitivity to insulin and clinically improve the condition of NIDDM (non-insulin-dependent diabetes mellitus) patients.

In this study, the researchers tested the relation between central serotonergic activity and peripheral insulin sensitivity in 19 healthy male volunteers (32.33 ± 11.11 years of age) with normal levels of blood glucose and glycated hemoglobin. The mean body mass index (BMI)* of the subjects was 28.53 ± 4.39 (BMIs from 25 to 30 are considered overweight, but not obese).

The release of prolactin in response to the serotonergic activity of D-fenfluramine was used to estimate central serotonergic activity. The authors found a negative correlation between insulin sensitivity and prolactin response in these healthy volunteers, which suggests that a lower insulin sensitivity is connected with decreased central serotonergic activity.

The authors suggest that one basis for a relation between 5-HT and sensitivity to insulin could be the increase by insulin of the ratio of tryptophan to other large neutral amino acids (LNAAs) in the bloodstream, thereby increasing the relative transport of tryptophan into the brain (tryptophan and other LNAAs compete for passage across the blood-brain barrier). The insulin-related increase of plasma tryptophan relative to these other amino acids is dependent on the sensitivity of insulin receptors. Another possibility is that the relation between central 5-HT and glucose tolerance could be mediated by corticosteroids. Major depression is thought to be connected with a reduction of tone of the serotonin system and also with an increase of hypothalamic-pituitary-adrenal (HPA) activity, expressed as nonsuppression of ACTH secretion in response to exogenous dexamethasone, a corticosteroid, e.g., a failure of circulating corticosteroids to provide negative feedback to the HPA axis to prevent further release of ACTH that stimulates the release of more circulating corticosteroids. However, in this study, they did not measure corticosteroids.

The authors conclude by suggesting that “modalities which increase sensitivity to insulin can facilitate serotonin activity in the brain and thus exert some antidepressant effects.”

*BMI is body mass index, measured as the weight in kilograms divided by the square of the height in meters.

Reference

1. Horacek et al., “The Relationship Between Central Serotonergic Activity and Insulin Sensitivity in Healthy Volunteers,” Psychoneuroendocrinology 24:785-797 (1999).