Mortality in Antioxidant Trials
A recent analysis was published1 on the effects of dietary supplements used in large, randomized, disease-prevention trials, either primary (before a deleterious event, such as a heart attack or the development of a particular cancer, occurs) or secondary (prevention of the reoccurrence of a deleterious event). The authors reported that, in the studies they examined, there was significantly increased all-cause mortality with beta-carotene, vitamin A, and vitamin E, either singly or combined. Vitamin C and selenium had no significant effect on mortality. These results received widespread reporting in the press (see, e.g., “High Doses of Antioxidants May Hurt More than Help” in the 2-28-07 Wall Street Journal).
The authors used database searches to identify potentially qualifying studies and then divided them into low-bias risk and high-bias risk, with the low-bias risk being those trials with high methodological quality. All the low-bias-risk vitamin A trials were pooled; the same was done with the other nutrients. The resulting all-cause mortality was based upon the pooled results of the low-bias-risk (high methodological quality) studies.
There are several serious limitations to such a meta-analysis. Some of these were identified by the authors, who noted: “The examined populations varied. The effects of supplements were assessed in the general population or in patients with gastrointestinal, cardiovascular, neurological, skin, ocular, renal, endocrinological, and rheumatoid diseases.” There is no way to assess (from the data given in this meta-analysis) to what extent the differences among these populations would have resulted in different effects from increasing the supplies of particular nutrients. For example, while beta-carotene has been found to increase lung cancer risk in smokers, it does not do so in nonsmokers. A pooling of the effects of beta-carotene in different populations, therefore, would not reflect the effects in all the populations.
Moreover, in the cardiovascular studies, a major confounding factor that has not, to our knowledge, ever been corrected for in a dietary supplement study is that most patients with cardiovascular disease these days are taking a statin. Statins reduce the synthesis of coenzyme Q10. Since coenzyme Q10 is important in the regeneration of tocopheryl radical to tocopherol, this could have had a major impact on the results of a vitamin E study in cardiovascular patients. The patients on statins would likely have had increased amounts of tocopheryl radicals as compared to patients not on statins, a result that could arguably have had an effect on their mortality.
The authors claim: “These populations mostly came from countries without overt deficiencies of specific supplements.” On the contrary, there are large segments of even highly advanced countries, such as the United States and Britain, that have dietary levels of certain nutrients that do not meet even the generally meager RDA levels. This is particularly true for the elderly. For example, a new study2 reported that, in the winter and spring, when hypovitaminosis D is highest, 7437 white, 45-year-old British individuals were measured for vitamin D levels. 25(OH)D concentrations below 25, below 40, and below 75 nmol/L were found in 15.5%, 46.6%, and 87.1% of participants, respectively. The concentration of vitamin D identified as optimum for bone health is greater than or equal to 75 nmol/L.2 During the summer and fall, the respective numbers were 3.2%, 15.4%, and 60.9%. Vitamin D concentrations below 40 were twice as likely in the obese as in the nonobese.
The problem, as we see it, is that the design of these dietary supplement studies are modeled after drug studies, in which (usually) one or perhaps two entities are tested against a placebo. As many scientists have pointed out, antioxidants work in systems to do what they do, which is not only frequently to quench free radicals but also to alter the expression of many genes by nonantioxidant mechanisms. (Then, of course, there is the considerable “problem” of getting people to stick with a placebo for long periods of time, when they can experiment on their own with easily accessible dietary supplements.)
- Bjelakovic et al. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA297(8):842-57 (2007).
- Hypponen and Power. Hypovitaminosis D in British adults at age 45 y: nationwide cohort study of dietary and lifestyle predictors. Am J Clin Nutr 85:860-8 (2007).
Climate change is allowing subordinate males on a remote Scottish island a chance to mate. Higher temperatures and lower rainfall mean that female grey seals forage over a wider range, making it more difficult for the top male to keep an eye on them all.— Nature, December 28, 2006, p. 982Scientific discovery consists in the interpretation for our own convenience of a system of existence which has been made with no eye to our convenience at all.— Norbert Wiener, The Human Use of Human Beings (1950)In 2000, the U.S. Food and Drug Administration (FDA) required novel antibiotics to demonstrate cure rates that were not lower by 10% or more (“noninferior to”) than that of a designated existing antibiotic (the earlier standard was 10–20%). Then in July 2005, unbeknown to industry, FDA again changed its position, requiring placebo-controlled trials rather than noninferiority trials for certain infections.— Nature Biotechnology, editorial, December 2006Comment: Requiring placebos (rather than evidence of noninferiority) when a treatment is available is a crime against humanity, a virtual replication of the “Tuskegee experiments,” where elderly black men with syphilis were deliberately not treated with penicillin even though it was known to be effective.All silencing of discussion is an assumption of infallibility.— John Stuart Mill, On Liberty (1859)
Fish Oils Approved by FDA for Reducing Triglycerides—Prescription Required
Prescription fish oils are now available, approved by the FDA for reducing high levels of triglycerides. The September 2006 Life Extension magazine reports that a bottle containing 180 1000-milligram capsules costs a “whopping” $236.89, about nine times as expensive as what this amount of fish oil sells for in a health food store. Moreover, the article goes on, the FDA permits the following statement to be made in package materials accompanying the prescription fish oils: “The U.S. Food and Drug Administration (FDA) has not approved nonprescription, dietary supplement omega-3s for the treatment of any specific disease or medical condition, like very high triglyceride levels.* Dietary supplement omega-3, or so-called fish oil, is not a substitute for prescription (fish oil) because they are not bioequivalent.”† [Emphasis as in original statement reprinted in article]
*By the FDA’s very narrow (and incorrect, in our opinion) interpretation of the Congressional statute permitting health claims, the FDA will not permit a “treatment claim” (such as: substance X may lower triglycerides) for any dietary supplement, no matter how much evidence exists demonstrating that the supplement is effective as a treatment. Thus, the fact that non-FDA-approved fish oils do not have FDA’s approval for use as a treatment for high triglyceride levels is meaningless, since the FDA will not give such approval. This company obviously hopes consumers will think that the FDA’s approval for their “prescription fish oils” means there is something special about their product (or, at least, special enough to be worth all that extra money).
†The article points out that there is more EPA and DHA in each prescription fish oil capsule than in most dietary supplement capsules of fish oils; however, all this means is that you might need to take 5 or 6 capsules of dietary supplement fish oils to get the same amount of EPA and DHA as in 4 capsules of the prescription version. The end result, according to the article, is that the prescription fish oil is still 797% higher than the nonprescription version sold by Life Extension. Moreover, nonprescription authentic fish oils are entirely bioequivalent to the prescription version (that is, their biological and biochemical properties are identical). This is a deadly fraud against the public by the FDA and opportunistic drug companies.
Comment: This company, relying upon the government’s guns to keep competitors’ speech from the market, implies that only FDA-approved fish oils can reduce triglycerides. While this is a lie, it is unfortunately true that most government (i.e., taxpayer-funded) “health care” programs and most insurance policies will only pay for FDA-approved treatments, and hence these contemptible, murderous creeps may actually profit from their lies.
Losing Weight and Improving Your Health with a Carbohydrate-Restricted Diet
We have long considered a modification of dietary carbohydrates [decreasing easily digestible carbohydrates—which are rapidly broken down into glucose—while increasing indigestible carbohydrates (fiber)] to be a cornerstone of a healthy diet. For example, see Chapter 8 of our 1986 book The Life Extension Weight Loss Program(Doubleday). Our recent discovery of the availability of a very-high-soluble-fiber (15% beta-glucans) and insoluble-fiber (15%), reduced-digestible-carbohydrates (about 30% resistant starch) whole grain (a strain of barley with about three times the soluble fiber content of whole oats) has resulted in a transformation of our diet. We are now ingesting far more soluble fiber than we ever have before, and, by combining the barley with other foods, we have reduced the glycemic index of our general diet. There are a rapidly increasing number of papers being published on the benefits of a restricted-carbohydrate diet, a few of which are described below.
Restricting dietary carbohydrates promotes better health whether or not there is weight loss
A recent review1 reported on the effects of restricting dietary carbohydrates, with and without weight loss, on measures of atherogenic dyslipidemia (such as high triglycerides or LDL-cholesterol). The minireview summary1 of the results of restricting carbohydrates included the following:
1. Carbohydrate restriction has been shown to have beneficial effects on fasting and postprandial (after-meal) triacylglycerol (fats), HDL-cholesterol, apolipoproteins, and lipoprotein subclasses. Higher triacylglycerol levels are associated with insulin resistance and also increase the production and secretion of atherogenic VLDL (very-low-density lipoproteins) from the liver. The review’s author reports that, according to a meta-analysis, plasma triacylglycerol can be expected to decrease by 0.015 mmol/L per kilogram of weight loss. A separate paper found that, although weight loss from a diet restricted in fat (<30% of kilocalories from fat) was similar to that from a diet restricted in carbohydrates (<30 g of carbohydrate/day), the improvements in plasma triacylglycerol levels were significantly greater in the group on the restricted-carbohydrate diet. After one year, the weight lost in the low-fat group was 3.1 ± 8.4 kg, and that lost in the restricted-carbohydrate group was 5.1 ± 8.7 kg. The expected reduction in triacylglycerol for the low-fat group was 0.047 mmol/L, while the actual reduction was 0.05 ± 0.96 mmol/L, in close agreement. By contrast, the expected reduction in triacylglycerol for the restricted-carbohydrate group was 0.077 mmol/L, yet the actual reduction was 0.65 ± 1.78 mmol/L, greater than 8 times the expected reduction. And this occurred despite the fact that the actual consumption of carbohydrate by participants was 120 g/day, 4 times as great as the amount they were supposed to consume.
Furthermore, the review continues, even in the absence of weight loss, studies have shown that consuming a diet restricted in carbohydrates can reduce plasma triacylglycerol. One study was reported to have found a greater reduction in plasma triacylglycerol during the weight-stable (maintenance) phase for the 26% carbohydrate group compared with the 54% carbohydrate group. Other studies were reported with similar findings in normal-weight healthy men and women and in type 2 diabetics.
2. Another consistent result of restricting dietary carbohydrates is an increase in HDL-C (HDL-cholesterol).2 In addition to increasing protective HDL-C levels, the author reports that, in a study of a restricted-carbohydrate diet he published with coworkers, they observed a significant increase in large HDL particles, with a reduction of medium HDL particles and no change in the quantity of small HDL particles. Large HDL particles are advantageous because they have a longer plasma half-life. The author and his coworkers believe that the results of this study (which found increased peripheral cholesterol removal and esterification and a reduced incorporation of triacylglycerol into HDL particles) support the idea that reducing carbohydrates increases HDL, not by inducing additional HDL synthesis but by increasing the plasma half-life of HDL particles. The author also cites papers in which increased HDL-C has been reported in normal-weight men and women who followed a weight-maintenance diet restricted in carbohydrates.
- Wood RJ. Effect of dietary carbohydrate restriction with and without weight loss on atherogenic dyslipidemia. Nutr Rev 64(12):539-45 (2006).
- Volek and Feinman. Carbohydrate restriction improves the features of metabolic syndrome. Metabolic syndrome may be defined by the response in carbohydrate restriction. Nutr Metab (Lond) 2:31 (2005).
Comparison of Atkins, Zone, Ornish, and LEARN Diets in
Overweight Premenopausal Women
A new study1 reports the results of a year-long study of the effects on weight loss among four diets: the Atkins (77 subjects), Zone (79 subjects), Ornish (76 subjects), and LEARN (79 subjects). As you are undoubtedly aware, the Atkins diet is very low in carbohydrates. The Zone diet is low in carbohydrates, the LEARN diet is low in fats and high in carbohydrates, and the Ornish diet is very high in carbohydrates and very low in fats.
The summary of the results reported that “. . . premenopausal overweight and obese women assigned to follow the Atkins diet, which had the lowest carbohydrate intake, lost more weight and experienced more favorable metabolic effects at 12 months than women assigned to follow the Zone, Ornish, or LEARN diets.”
The mean 12-month weight losses were: Atkins, –4.7 kg (95% confidence interval, –6.3 to
It is interesting to note that the diets were all low in fiber. Calculated fiber contents of the diets at 12 months were: Atkins, 15.2 (±2.7); Zone, 16.7 (±9.4); LEARN, 18.3 (±7.8); and Ornish, 19.3 (±9.4). The fiber content of those on the Ornish diet was significantly different from that of those on the Atkins diet.
The Atkins diet was significantly higher in fat (44.3 ± 12.5, up from 36.2 ± 7.8 at baseline) at 12 months than the other diets, while protein content of the Ornish diet (18.3 ± 4.0) was significantly lower than that of the Atkins diet (20.6 ± 5.3). The Atkins diet was also significantly higher in saturated fat content (27.2 ± 13.3, up from 26.5 ± 11.1 at baseline) than the other three diets. Interestingly, the Ornish group was only able to get their saturated fat percentage down from 24.8 ± 10.3 at baseline to 16.9 ± 11.4, although the goal was to reach 10% or less saturated fat. This underscores the difficulties for individuals trying to reduce saturated fat to such a low level.
Insulin and glucose measurements showed that neither the overall trajectory across all time points nor the 12-month differences were significantly different among the groups, either for fasting insulin or fasting glucose. HDL-cholesterol was significantly greater (compared to baseline) at 12 months in the Atkins, Zone, and LEARN diets as compared to the Ornish diet. Diastolic blood pressure was significantly lower (compared to baseline) in the Atkins, Zone, and LEARN diets as compared to the Ornish diet. Systolic blood pressure was significantly lower (compared to baseline) in the Atkins diet as compared to the other three diets.
This study provides clear supporting evidence for the benefits of reducing carbohydrate calories for weight loss (Atkins diet) and also demonstrates favorable changes for those on the Atkins diet in lipid levels and blood pressure.
- Gardner et al. Comparison of the Atkins, Zone, Ornish, and LEARN diets for change in weight and related risk factors among overweight premenopausal women. JAMA 297(9):969-77 (2007).
Dietary Factors and Adiponectin, a Fat-Derived Peptide that Improves Insulin Sensitivity: Moderate Alcohol Strikes Again
We have written, in our article on supplements for healthy weight management (see “Supplements We Take with Our Meals to Enhance Health and Healthy Weight Management” in the May issue of Life Enhancement), on the increase in adiponectin gene-expression levels that occurred when fat cells were treated with anthocyanins found in purple corn color. Similar anthocyanins are found in blueberries and other blue and purple fruits and vegetables. Adiponectin is important for insulin sensitivity, and its levels are reduced in the obese and in diabetics. Here, we describe a recent paper1 that reports an increase, by moderate alcohol consumption, in adiponectin concentrations in men with no history of cardiovascular disease. The paper also found that a carbohydrate-rich diet with a high glycemic load is associated with lower adiponectin concentrations in this same population of men.
Moderate alcohol consumption continues to deliver interesting health benefits. This study included 532 male participants from the Health Professionals Follow-Up Study. The paper reports that there was a significant nonlinear association between plasma adiponectin concentration and alcohol intake. Whereas nondrinkers had mean plasma adiponectin concentrations of 16.48 mg/L, those who consumed 0.1–4.9, 5.0–14.9, 15.0–29.9, or equal to or greater than 30 grams of alcohol per day had mean concentrations of 16.79 (P=0.77 compared with nondrinkers, not significant), 18.97 (P=0.02), 19.11 (P=0.01), and 18.39 (P=0.10, not significant) mg/L, respectively.
The authors also described another recent study2 that examined the effects of 40 g of whiskey per day as compared to water on plasma adiponectin concentration in a randomized crossover trial. They found significantly greater plasma adiponectin concentrations after the consumption, for 17 days, of whiskey (8.78 mg/L) as compared to water (7.94 mg/L).
- Pischon et al. Association between dietary factors and plasma adiponectin concentrations in men. Am J Clin Nutr 81:780-6 (2005).
- Sierksma et al. Effect of moderate alcohol consumption on adiponectin, tumor necrosis factor-alpha, and insulin sensitivity. Diabetes Care 27:184-9 (2004).
Suppression of Fatty Acid Synthase in Breast Cancer Cells by Tea and Tea Polyphenols
Fatty acid synthase (FAS) is the final enzyme in the biochemical pathway for lipogenesis, synthesizing fats from glucose. It is highly conserved, as bacteria contain a version (FASII) of the same enzyme as is found in mammals. Importantly, FAS is overexpressed by many human cancers (such as breast, colon, ovary, lung, and prostate), and inhibition of FAS induces apoptosis (programmed cell death) in human cancer
FAS inhibitors result in increased levels of malonyl-CoA, the substrate for FAS, because of reduced conversion of malonyl-CoA to fat. As we have discussed earlier, malonyl-CoA is an important signaling molecule that provides the brain with information concerning the availability of caloric fuel and thereby affects regulatory pathways for feeding and energy expenditure. When malonyl-CoA levels are high, feeding is suppressed and energy expenditure increased. In cancer cells, fatty acid synthesis is associated with markers of proliferation.1
A recent paper1 reports that FAS is overexpressed in the malignant human breast carcinoma MCF-7 cells, and this expression is increased by concomitant expression of epidermal growth factor. In this study, the researchers found that, in cultures of MCF-7 cells, tea extracts from oolong, black, and green tea “seemed to stimulate the expression of FAS at a lower concentration (30 μg/ml). However, when the cells were exposed to a higher concentration of tea extracts (120 μg/ml), the expression of FAS was inhibited by green and black tea extracts, but not by the oolong tea extract.” Moreover, “In green tea catechins, only EGCG was found to reduce the amount of FAS protein significantly, by 76% at a dose of 30 μM … To our surprise, the black tea polyphenols TF-1, TF-2, and TF-3 [these are all theaflavins] actively downregulated FAS by 52, 69, and 87% at 30 μM, respectively. TF-3 was the most active in reducing the FAS protein.”
The authors also report that the suppression of epidermal growth factor-induced FAS protein by EGCG and TF-3 was also demonstrated in human hepatoblastoma HepG2 (a liver cancer line). Interestingly, they report that “It appeared that the expression of FAS in the HepG2 cells was more tightly regulated by insulin than by EGF [epidermal growth factor].” The insulin-enhanced FAS expression was significantly suppressed by EGCG and TF-3. The stimulation of FAS expression by insulin (at least in this human liver cancer line) may be one reason to suggest (as we have) that FAS inhibitors will work best with a low-glycemic-index diet.
It would also appear that the use of both green tea and black (fermented) tea would be most beneficial, as each type of tea contains its own (different) FAS inhibitors. It is not clear why oolong tea did not suppress FAS in this study; perhaps the particular type of oolong tea they used didn’t include the theaflavins as found in the black tea.
- Yeh et al. Suppression of fatty acid synthase in MCF-7 breast cancer cells by tea and tea polyphenols: a possible mechanism for their hypolipidemic effects. Pharmacogenom J 3:267-76 (2003).
- Thupari et al. Fatty acid synthase inhibition in human breast cancer cells leads to malonyl-CoA-induced inhibition of fatty acid oxidation and cytotoxicity. Biochem Biophys Res Commun 285:217-23 (2001).
Combinations of Biomarkers Predictive of Later-Life Mortality
An interesting recent study1 examined 13 biomarkers as predictors of mortality over a 12-year period in a sample of 530 men and 659 women 70–79 years old. These individuals were part of a cohort of older adults from the MacArthur Study of Successful Aging, a prospective epidemiological investigation of factors associated with healthy aging.
The biomarkers examined different systems, including: cardiovascular [systolic blood pressure (SBP) and diastolic blood pressure (DBP)]; neuroendocrine [epinephrine (EPI), norepinephrine (NE), cortisol, and dehydroepiandrosterone (DHEA)]; metabolic [HDL-cholesterol, total/HDL-cholesterol, glycosylated hemoglobin (HbA1c, a measure of long-term glucose levels)]; and immune [IL-6, fibrinogen, C-reactive protein (CRP), and albumin]. Note: low levels of DHEA, HDL-cholesterol, and albumin are high-risk (HR), whereas low levels of the other markers are generally favorable.
Their general strategy was to examine different combinations of these markers to develop differential predictions of mortality for male and female subjects. The high-risk (HR) combinations in men were those in which the subgroups having that combination had greater than or equal to 70% dead within the 12 years. For the men, 11 of the 13 biomarkers enter into HR pathways: cortisol, CRP, IL-6, fibrinogen, NE, EPI, HbA1c, HDL-cholesterol, DHEA, and SBP and DBP. For the women, only 6 of the 13 biomarkers enter into HR pathways (greater than or equal to 60% dead): SBP, DBP, HbA1c, CRP, IL-6, and DHEA.
For 106 men in HR pathways, there was a cluster of five biomarkers that occurred together at elevated levels: CRP, IL-6, fibrinogen, NE, and EPI. In this subgroup of men, 71.7% had all five of these biomarkers at elevated risk levels, 97.2% had four or more of the five biomarkers, and 100% had three or more of the five biomarkers at elevated risk levels.
For 29 women in HR pathways, there was a cluster of four biomarkers occurring frequently: SBP, CRP, IL-6, and HbA1c.
Overall, significant gender differences were found. “Elevated SBP occurs in 100% of the HR female pathways and in only 17% of the HR male pathways. Fibrinogen, NE, and EPI, individually and in combination, dominate male pathways but do not even occur in female pathways. CRP and IL-6 occurred frequently in both male and female HR pathways.”
As the authors explain, limitations of the study included: (1) biomarker information was obtained at a single measurement point at the beginning of the study; (2) these adults were recruited for participation on the basis of high levels of cognitive and physical functioning, hence results may not be the same for lower-functioning adults; and (3) the analysis did not include other risk factors or health-promoting behaviors.
- Gruenewald et al. Combinations of biomarkers predictive of later life mortality. Proc Natl Acad Sci USA 103(38):14158-63 (2006).
Cocoa Reduces LDL Oxidative Susceptibility and Increases HDL-Cholesterol
Twenty-five normocholesterolemic and mildly hypercholesterolemic Japanese men with a mean age of 38 ± 1 years participated in a 12-week study of cocoa powder ingestion.1The participants received either 12 g of sugar per day (controls) or 26 g of cocoa powder plus 12 g of sugar per day (experimental group). The results showed that, after 12 weeks, the cocoa-consuming group had a 9% prolongation from baseline levels in the time it takes for LDL to be oxidized (lag time). This was a significantly greater prolongation than the reduction (decreased prolongation) measured in the control group (–13%). HDL-cholesterol was significantly increased (24% increase) as compared to the controls (5% increase).
An earlier study cited by the authors reported that HDL-cholesterol increased by 11% and 14% after a 3-week intake of dark chocolate or dark chocolate enriched with cocoa polyphenols, respectively. The daily consumption of catechin monomers and proanthocyanidins was reported to be 270 mg from the dark chocolate and 420 mg from the dark chocolate with added cocoa polyphenols. As the authors note,1 “These results indicated that the increase in plasma HDL-cholesterol concentration caused by polyphenols was dose-related. Our study also showed that cocoa powder enhanced plasma HDL-cholesterol concentrations and that there was a nonsignificant trend toward a positive correlation between the excretion of urinary catechin and plasma HDL-cholesterol. Intake of flavonoids other than catechins, such as isoflavones, flavanones (naringenin and hesperetin), and polyphenols in red wine, have also been shown to increase HDL concentrations in both human and animal studies.”
The results also showed that the cocoa powder ameliorated some of the deleterious effects of the sugar intake by reducing the excretion (a 24% reduction from baseline) of urinary dityrosine, which was significantly greater than in the control group (–1%), and there was also a trend of lower production of Maillard reaction products (chemical reactions between sugar and protein) as measured by Nε-(hexanoyl)lysine excretion.
So, while having fun eating your Durk Pearson & Sandy Shaw’s® LifeByChocolate™ low-glycemic-index, low-digestible-carbohydrate, no-sugar, high-protein chocolate pudding, remember that you’ll be getting about 7 grams of cocoa per half-cup serving.
- Baba et al. Continuous intake of polyphenolic compounds containing [sic] cocoa powder reduces LDL oxidative susceptibility and has beneficial effects on plasma HDL-cholesterol concentrations in humans. Am J Clin Nutr 85:709-17 (2007).