October 2000 Blog with Durk and Sandy

It is the fundamental theory of all the more recent American law . . . that the average citizen is half-witted, and hence not to be trusted to either his own devices or his own thoughts.
- H. L. Mencken

A DIET RICH IN VEGETABLES AND FRUITS, OR DIETARY SUPPLEMENTS?

Another round of vehement disagreements has emerged in the ongoing argument over whether supplements are important for optimal health or whether one can do even better by forgetting supplements and concentrating on eating a well-balanced diet containing lots of fruits and vegetables. A recent report from the National Academy of Sciences' Institute of Medicine recommended modest increases in intake of certain dietary constituents, such as vitamin C, but suggested that the recommended amounts can be easily obtained by most people from foods, making dietary supplements unnecessary. The July 5, 2000 Journal of the National Cancer Institute, in reporting this, says that the most consistent advice remains eating a diet high in fruits and vegetables.

Norman I. Krinsky, Ph.D., chair of the NAS Panel on Dietary Antioxidants and Related Compounds, and a professor of biochemistry at Tufts University School of Medicine, sums it up: "A direct connection between the intake of antioxidants and the prevention of chronic disease has yet to be adequately established. We do know, however, that dietary antioxidants can in some cases prevent or counteract cell damage that stems from exposure to oxidants. But much more research is needed to determine whether dietary antioxidants can actually stave off chronic disease."

We do not think the recommendation to eat lots of fruits and vegetables rather than taking supplements is nearly as informative as those making it appear to believe. Note, for example, the following facts:

1. Fruits and vegetables each contain thousands of different chemical substances, not all of which have even been identified, let alone had their biological effects determined.

2. It is highly unlikely that every one of these thousands of different substances contributes to the health-protective effects of fruits and vegetables; in fact, some of them have toxic effects (such as solanine in tomatoes and potatoes).

3. Major protective agents in fruits and vegetables have not been identified, nor have the optimal doses of these agents been determined.

4. The protective effects of fruits and vegetables against the development of certain cancers can vary considerably, depending upon the type of cancer, smoking history, lifestyle, dietary habits, family history of cancer, gender, and demographic data.

In a recent example, the Netherlands Cohort Study of 62,573 women and 58,279 men aged 55-69 years, with 6.3 years of follow-up, found the following: 57 cases of lung cancer in never-smokers, 532 cases in current smokers, and 321 cases in former smokers. Among never-smokers, vegetable and fruit consumption were not inversely associated with lung cancer. Among former and current smokers, inverse associations with statistically significant trends were found between total vegetable consumption and lung-cancer risk. Inverse associations with cooked and raw vegetables showed statistically significant trends in current, but not in former, smokers. The inverse association with fruit consumption had a significant trend only among current but not among former smokers. Inverse association with citrus fruit was found in current smokers but not former smokers. The inverse association was stronger for some vegetables, such as cauliflower, endive, string beans, and lettuce, than for others. (It was proposed that this last effect might be due partly to their popularity among participants.) These complexities require explanations that do not currently exist. [Voorrips et al., "Vegetable and fruit consumption and lung cancer risk in the Netherlands Cohort Study on Diet and Cancer," Cancer Causes and Control 11:101-115 (2000).]

COMPARING FRUITS AND VEGETABLES TO DIETARY SUPPLEMENTS

Comparing the health-promoting effects of diets rich in fruits and vegetables to the health effects of single antioxidant supplements (such as vitamin C or E) is worse than comparing apples to oranges, since antioxidants are known to work together in free-radical-controlling systems. Yet most randomized, double-blind, controlled studies of nutrient-disease relationships have tested only a single nutrient's effects on the incidence of chronic diseases, e.g., the Physicians Health Study that studied the effect of beta-carotene on the risk of lung cancer. Most supplement users take supplements as combinations of nutrients, not as an individual substance. Because antioxidants work in conjunction with other antioxidants and nutrients, a combination of such supplements is likely to have a more beneficial, more physiological effect than daily supplements of just one substance.

Studies continue to be published comparing the effects of the combinations of antioxidants and other nutrients in fruits and vegetables with a single nutrient supplement. For example, in a brief communication in the 22 June 2000 Nature,Eberhardt et al. ("Antioxidant activity of fresh apples," pp. 903-904) compared (on a per gram basis) the total antioxidant activity of apples to that of vitamin C. They found that 100 grams of fresh apples had an antioxidant activity equivalent to 1500 mg of vitamin C and that whole-apple extracts inhibit the growth of colon and liver cancer cells in vitro in a dose-dependent manner. Since they found that the actual amount of vitamin C in 100 grams of apples with skin was 5.7 mg, they point out that most of the antioxidant effect must be due to other substances in the apples. They conclude from this that "natural antioxidants from fresh fruit could be more effective than a dietary supplement." Sure, if all you take is vitamin C, then that is likely to be true.

With more knowledge of the combined effects of antioxidants and other nutrients, it will become possible to design dietary supplements that are more effective than apples. (Remember that apples did not evolve their nutritional contents to provide health benefits for humans or other mammals, but to propagate apple seeds.) In fact, we simply do not have enough information or enough money to compare the antioxidant capacity or the cancer-retarding properties of apples to the many combinations of nutrients available as dietary supplements today. Some of these combinations may already be better antioxidants (on a per gram basis) than apples. Designing dietary supplements is at the present time as much an art as it is a science, but that is not evidence that fruits and vegetables are inherently more healthful than a properly designed dietary supplement.

It is certainly true that there is very limited information available on the effects of the combinations in multinutrient and multiantioxidant dietary supplementation, but it is also true that there is not a lot known about how the pluses and minuses of the thousands of substances in a fruit or vegetable work in human biology. The way we see it, the best advice is both to eat a diet rich in fruits and vegetables and to take dietary supplements whose health-promoting effects are supported by substantial research, even if not conclusively proven.

DO-IT-YOURSELF DRUG RESEARCH & DEVELOPMENT

A disease advocacy group, tired of waiting for drug development to treat its disease, has decided to invest in its own research and development program. Started off by a $20 million donation from the Bill and Melinda Gates Foundation, the Cystic Fibrosis Foundation announced that it will invest at least $30 million in a small biotech firm, Aurora Biosciences of San Diego, to identify compounds that might prove useful in treating CF. According to the 9 June 2000 Science, in which this is reported, the new investment represents another spinoff of the "growing trend of patient groups taking charge of biomedical research."

If Aurora is able to identify likely candidates from the several hundred thousand molecules in its library over the next five years, the CF Foundation will pay the company an additional $16.9 million to prepare the candidates for clinical trials. Because of the immense expense of actually getting FDA approval to take a successful treatment to market, the foundation would then have to get coinvestment by a major pharmaceutical company.

THE POLITICS OF CANCER

Some facts¹ support our view that government funds research as a part of a political and self-interested agenda rather than as "pure" science unpolluted by motivations beyond understanding how things work. The federal government's National Cancer Institute currently allocates less than 3% of its budget to primary prevention of cancer. Instead it focuses on diagnosis and treatment, essentially doing basic research that is part of drug development. (The American Cancer Society, a nonprofit charity, allocates less than 0.2% of its budget to cancer prevention.) Meanwhile, the NCI has such a close relationship to the pharmaceutical industry as to appear to be in bed with it. Dr. Samuel Broder, the former NCI director, recently admitted "that the NCI has become what amounts to a government pharmaceutical company." Former FDA commissioners almost always end up in extremely lucrative positions at pharmaceutical companies.

Economist James Buchanan won the Nobel Prize for his innovative "public choice" theory, which shows that government agents (such as those who distribute government - actually, taxpayer - research money) act individually to further their own interests rather than promoting the interests of the public as a whole. This does not mean that every government agent is dishonest or without principles, but that each is a human being who has his or her own ideas of what should be done with the public's money, ideas that may or may not be consistent with the public interest as a whole. The control of other people's money by government is, no matter how good the cause may appear, a huge moral hazard.

As reported by Samuel S. Epstein, M.D., in the July 26, 2000 JAMA, p. 442.

THE POLITICS OF GOVERNMENT-FUNDED RESEARCH

We have often warned people that government-funded research is not "pure" science uncorrupted by economic interests (as compared, for example, to science funded by a profit-seeking private entity). Government not only has to place a value on research in order to decide which scientific projects to fund, but to determine how policy decisions will be affected by the results of that research.

Government often funds science that supports or seems to support or can be made to appear to support its political agenda. For example, the U.S. Department of Agriculture funds much research on commercial crops, fruits and vegetables, and dietary antioxidants. However, the USDA has no political interest in promoting the dietary supplement industry; rather, it has an interest in promoting the food industry in which its regulatory efforts are invested. Moreover, the food programs of the federal government that include school lunches and food stamps require a certain level of nutrition, all of which must by law be supplied by food and not by dietary supplements. As we have noted before, scientific findings that support a higher level of recommended daily intake of nutrients would require the provision of more expensive foods (such as fruits and vegetables!) to supply them and would, therefore, add billions of dollars a year to the government's expenses. Hence, the government continues to focus on whether evidence for increased levels of nutrients such as vitamins C and E and folic acid is "conclusive," rather than whether the bulk of the evidence supports higher intakes. The pretense that we can (or should) do nothing until the evidence is "conclusive" is the excuse frequently used by the FDA for failing to approve health claims that provide a truthful picture of the available inconclusive evidence, a violation of the First Amendment.

HIGH BODY FATNESS, NOT LOW BODY MUSCULARITY, PREDICTS DISABILITY IN THE ELDERLY

Although one would have thought that low muscularity would be the source of most of the mobility problems of the elderly, a new study¹ reports that it is high body fatness, not low fat-free mass, that predicts such problems.

The scientists used data from the Cardiovascular Health Study to study the problem. They examined body composition and self-reported, mobility-related disability in 2714 women and 2095 men aged 65 to 100 years. The odds ratio for disability in the highest quintile of fat mass was 3.04 for women and 2.77 for men, compared with those in the lowest quintile. Low fat-free mass was not associated with a higher prevalence of disability. The increased risk of disability was not explained by age, physical activity, chronic disease, or other potential confounders.

Obesity Is a Mortality Risk Factor in the Elderly Too
Another study² reports that, contrary to an earlier study that appeared to indicate that obesity is not as risky in older as in younger individuals, obesity increased mortality in both old and young individuals. However, due to the increasing impact of age on mortality, the relative risk of obesity as a mortality risk factor is lower in older than in younger persons. For example, during the 11-year follow-up, 1.5% of reference-weight young men (30-39 at the start of the study) died, whereas 3.6% of obese men in the same age group died. In the reference-weight group of older men (60-69 at the start of the study), 25.3% died in the follow-up period, while 31.9% of the obese men in the same age group died. Hence, the relative mortality risk of obesity is higher in younger than in older men, but the mortality risk differences between obese and reference-weight groups were higher in the older than the younger men. The overall finding was that the BMI [body mass index: weight in kilograms divided by (height in meters)²] associated with the lowest mortality was 18.5-24.9 in individuals 30-74 years old.

No matter how you look at it, excess body fat is a health risk, especially if you would like to live a very long time.

Visser et al., "High Body Fatness, but Not Low Fat-Free Mass, Predicts Disability in Older Men and Women: The Cardiovascular Health Study," Am. J. Clin. Nutr.68:584-90 (1998).
Stevens, "Impact of Age on Associations Between Weight and Mortality," Nutrition Reviews 58(5):129-137 (2000).

SALT, OBESITY, INSULIN SENSITIVITY, AND HYPERTENSION

The recent outpouring of studies on the complex interrelationships between insulin resistance and disease has provided new insight into hypertension, cardiovascular disease, diabetes, and obesity, among others. Recent published papers bring together sensitivity to salt, salt excretion, and a possible relationship to insulin resistance.

It has been known for quite some time that high blood pressure is frequently associated with insulin resistance. Data have suggested that salt sensitivity is associated with high blood pressure in a limited fraction of the latter population. A new paper now reports that salt sensitivity is associated with insulin resistance and with a reduced fall in blood pressure during the night in essential hypertension in both diabetic and nondiabetic subjects.¹

Another paper published at about the same time reports that natriuretic peptides have a potent lipolytic effect (releasing fatty acids from fat-storage tissue) via a nonadrenergic mechanism in abdominal subcutaneous adipose tissue of healthy human subjects.²Natriuretic peptides are involved in the regulation of blood pressure, blood volume, and kidney excretion of sodium. They inhibit renin, vasopressin, and aldosterone, and markedly stimulate diuresis (elimination of water through the kidneys) and natriuresis (elimination of sodium throught the kidneys), as well as being potent vasodilators. Their potent lipolytic effect links them to insulin sensitivity, since plasma fatty acids are powerful modulators of insulin sensitivity.

For example, increasing plasma fatty acid concentration for five hours caused a reduction in insulin-stimulated muscle glycogen synthesis and whole-body glucose oxidation compared to controls in one study.³ This is presumably one reason for the reduced insulin sensitivity in obesity, where plasma fatty acid concentrations are likely to be elevated. The release of "excess" natriuretic peptides in response to salt may be a mechanistic link between those who ingest excess salt or who have salt sensitivity and the reduction of insulin sensitivity.

Suzuki et al., "Association of Insulin Resistance with Salt Sensitivity and Nocturnal Fall of Blood Pressure," Hypertension 35:864-868 (2000).
Sengenes et al., "Natriuretic Peptides: a New Lipolytic Pathway in Human Adipocytes," FASEB J. 14:1345-1351 (2000).
Shulman, "Cellular Mechanisms of Insulin Resistance," J. Clin. Invest.106(2):171-176 (2000).

HOMOCYSTEINE ASSOCIATED WITH HOSTILITY AND ANGER

An interesting recent paper¹ reports that plasma homocysteine concentrations are positively and significantly associated with hostility in middle-aged men and women and with anger in men. This may be the mechanistic explanation, at least in part, for the known relationship between increased cardiovascular disease risk and hostility as well as the increased risk of coronary artery disease associated with both heightened expression and inhibition of anger. This suggests that folic acid, vitamin B6, and possibly vitamin B12 might be useful in the treatment of a psychological condition in some people, as well as reduce their risk of cardiovascular disease.

Stoney et al., "Plasma Homocysteine Concentrations Are Positively Associated With Hostility and Anger," Life Sci. 66(23):2267-2275 (2000) (abstract only, from CA Selects: Psychobiochemistry, Issue 15, 2000).

CONJUGATED LINOLEIC ACID (CLA): DOES IT REDUCE BODY FAT IN HUMANS?

Many benefits of CLA have been reported in experimental studies involving animals such as rodents, rabbits, and pigs, including anticancer, antiatherogenic, and antidiabetogenic actions. However, little work has been done in humans. Since there have been many differences discovered in the effects of CLA in different species, including differences between mice and rats,¹ it is most welcome that two new papers^2,3on the effects of CLA in humans have now been published.

The results of these two studies overall do not appear to provide support for an effect of CLA on reducing body fat, at least in these seventeen healthy, nonobese women between the ages of 20 and 41, who were the subjects of the 64-day study. Ten of the subjects were randomly assigned to receive 3 grams per day of CLA.

The study itself was done with great care, with the subjects staying in a metabolic suite at the Western Human Nutrition Center at the University of California at Davis, where the amount and content of their diets were controlled, and even the amount of exercise was controlled. The amount of energy that each subject obtained from food was regulated so as to maintain weight during baseline. Subjects were weighed daily, and body composition was determined three times per week by total body electrical conductivity. Energy expenditure was measured once during the baseline period and twice during the intervention period.

The women fed the CLA for 64 days showed no significant change in fat-free mass, fat mass, or percentage body fat compared to the placebo group. These findings are in contrast to those of the other human CLA feeding study, the Medstat study, which reported a 20% decrease in body fat after 12 weeks of CLA supplementation (at approximately 1.8 grams per day) in free-living, healthy men and women. The authors of the new study note that there are important differences between their study and the Medstat study that might explain the discrepancy. First, in the new study, body composition was measured three times a week using a whole-body measurement, while the Medstat study measured body composition once every four weeks using infrared technology on the biceps of the better arm. Second, the Medstat study included both males and females but did not break down the results by gender. Hence, it is not clear what effects the women in the Medstat study actually experienced. Third, the new study was conducted in a metabolic suite so diet and activity could be controlled and held constant throughout the study, while the Medstat study involved free-living subjects with "no documented evidence of activity or diet intake levels." Finally, the isomeric composition of the CLA supplement was not reported in the Medstat study and could be different from that of the new study. There are differences between the effects of these isomers (discussed in the paper). Hence, it is difficult to compare the results of the two studies.

The researchers further note that previous work with animals - such as mice, rats, and pigs - that showed a decrease in body fat was done with weanlings or adolescent animals that were not fully grown and had not established their adult body composition. They suggest that some data indicate a different effect of CLA on growing animals (by, for example, depressing body-fat accumulation via a reduction in preadipocyte number), and further work is needed to study the effects of CLA on adult animals.

The new study found no significant difference in energy expenditure or in fat oxidation during rest or walking between the treated and placebo groups. Walking did increase fat oxidation and energy expenditure in both placebo and treated subjects, as expected.

The CLA supplement used in this study included a number of isomers along with the isomer thought to be the active form, trans-10,cis-12. While previous studies showing body-fat reductions in mice used CLA supplements that contained 40-45% of the active form, the new human study's CLA supplement contained only about 23% of this form. This is another possible explanation for the results.

Fat Didn't Decrease, but Leptin Levels Did
Curiously, despite the lack of fat loss reported in the study, the companion study reports that there was a decrease in mean leptin levels over the first 7 weeks, followed by a return to baseline levels over the last 2 weeks. Leptin is a hormone released by fat cells that generally (though not always) correlates with the amount of fat mass. In mice fed 1% CLA by weight of their diet, plasma leptin levels were also significantly decreased after 6 weeks of treatment and then returned to base levels. The mouse study found a 50% decrease in fat after six weeks and a 43% decrease by the end of the study, even though at the end of the study there was no difference in leptin levels between the treated and control mice.

Bottom Line: Does CLA Decrease Body Fat?
It's hard to say based upon the available human and animal research, including the new human study. More research is needed. The evidence for the anticarcinogenic effect of CLA is fairly impressive, however.

Moya-Camarena and Belury, "Species Differences in the Metabolism and Regulation of Gene Expression by Conjugated Linoleic Acid," Nutrition Reviews57(11):336-340 (1999).
Zambell et al., "Conjugated Linoleic Acid Supplementation in Humans: Effects on Body Composition and Energy Expenditure," Lipids 35(7):777-782 (2000).
Medina et al., "Conjugated Linoleic Acid Supplementation in Humans: Effects on Circulating Leptin Concentrations and Appetite," Lipids 35(7):783-788 (2000).

VASOCONSTRICTION DURING REM SLEEP MAY INCREASE RISK OF HEART ATTACKS

REM sleep is a phase of sleep during which dreams take place and during which, surprisingly, many physiological processes resemble that of the awake state. There is much more sympathetic (adrenergic) activity during REM than non-REM sleep. A new study¹ reports that not only is there more sympathetic activation during REM sleep, but there is considerable peripheral vasoconstriction. Though the authors note that they do not have data showing that REM-related vasoconstriction also occurs in larger blood vessels, they did find that, in a canine model, experimental occlusion of the coronary arteries during REM sleep resulted in a greater-than-expected decrease in coronary blood flow.

The authors hypothesize that: "The intense sympathetic activation during REM sleep and the preponderance of REM in the early morning hours have led to the suggestion that REM sleep may be responsible for increased cardiac events seen at this time."