Epidemiologic Studies

As time marches on, our vision becomes clearer; not that aging increases visual acquity, but rather that long-term studies begin to yield significant new data that refute short-term studies.

We learn, for example, from a pooled analysis of eight prospective studies that included 430,281 men and women followed for up to 6-16 years across studies, that elevated consumption of fruits and vegetables was associated with "a modest reduction in lung cancer risk, mostly attributable to fruit, not vegetable intake." But the 20 researchers from five countries who participated in this substantial study tell us that, "The modest inverse association observed for fruit intake, and the absence of a reduction with vegetable intake, reinforces the public health message that the primary focus for reducing lung cancer incidence and mortality should be in smoking prevention and cessation" [20].

From another study of fruit and vegetable intake conducted by 10 members of the Harvard University School of Public Health, and the National Sun Yat-Sen University of Taiwan, in which prospective cohorts of 71,910 nurses and 37,725 male health professionals were followed for 15 years, the investigators found that increased fruit and vegetable consumption was "associated with a modest, although not statistically significant reduction in cardiovascular disease and not cancer " [ 21 ].

The European Prospective Investigation into cancer and Nutrition, referred to as EPIC, which involved 43 researchers from 10 countries, not including the United States, and enrolling 285,526 women between the ages of 25 and 70 years, were followed for >5 years to determine both the total and specific vegetable and fruit intake on the incidence of breast cancer. This formidable study found that neither the total nor the specific vegetable or fruit intake was associated with risk for breast cancer, and that the absence of a protective association was observed among almost all of the participating countries. They make the additional point that the duration of follow-up is relatively short and that, "we cannot exclude that associations will be found after more years of follow-up." They also note that it is of interest and concern that a protective effect is supported by a vast number of case-control studies [22].

This concern is being reiterated time again as differences of considerable magnitude in vital issues are published. Contrary results between observational, case—control studies and prospective cohort studies, and randomized clinical trials is an ongoing epidemiologic problem. For the most part, case-control studies show favorable responses to increased consumption of fruits and vegetables, while cohort studies and clinical trials are equivocal to negative. It should be recalled that because case-control studies are observational, relying on the memory of those who have had cancer or heart disease, bias can mislead when cases are compared to healthy control volunteers, who may be health-conscious and eat more fruits and vegetables.

Concerned about this continuing problem, and the fact that observational studies consistently show that individuals who use large doses of vitamin obtained cardiovascular benefits, researchers from the University of Miami Medical Center and Yale University Medical School conducted a metaanalysis of seven large-scale randomized controlled clinical trials of the effectiveness of vitamin E in the treatment and prevention of cardiovascular disease. Data on myocardial infarction, stroke, and cardiovascular death were included. They found that six of the seven trials "showed no significant effect of vitamin E on cardiovascular disease," and they also state that "vitamin E had neither a statistically significant nor a clinically important effect on any important cardiovascular event" [23]. They pointed out that the importance of this conclusion is enhanced by a recent survey indicating that 24% of adults in the United States are taking vitamin E supplements, which in effect precludes their use of known beneficial drugs.

At this point we should recall both the HOPE and HOPE-TOO trials discussed in Chapter 2, which orchestrated a large andomized, double- blind, placebo- controlled international trial: the initial heart outcomes prevention evaluation. Recall, too, that this trial enrolled 9541 individuals at 267 centers around the world, that HOPE-TOO enrolled 7030 individuals at 174 centers, and that after a median of 7 years of follow-up, the investigators found an increase in the risk of heart failure and concluded that "Vitamin E supplements should not be used in patients with vascular disease or Diabetes mellitus. Furthermore, their data clearly showed that vitamin E supplementation does not prevent cancer or major cardiovascular events [24]. And while back at Chapter 2, revisit the discussion of Miller et al. (Ref. 28 in Chapter 2), on high-dose vitamin E.

In July 2005, in yet another study, this one a randomized, clinical trial, conducted between 1992 and 2004, in which 39,876 healthy US women aged at least 45, were randomly assigned to receive vitamin E or placebo, and aspirin or placebo, were followed for an average of 10.1 years. The study found that 600 IU (international units) of vitamin E taken every other day "provided no overall benefit for major cardiovascular events or cancer, did not affect total mortality, nor decreased cardiovascular mortality in healthy women" [25] . Low- dose aspirin (100 mg) taken every other day had no effect on overall cancer incidence of mortality.

Three investigators, two from Canada, one from Spain, collaborated on a study to determine whether consumption of tomato products and lycopene reduces the risk of prostate cancer. From the results of their metaanalysis of 23 published studies that met their multiple criteria, they reported that "The existing evidence is not overwhelming enough to recommend the use of lyco-pene supplements in the prevention of prostate cancer" [26].

What can we glean from published studies specifically concerned with antioxidant supplementation and its effects on chronic medical illnesses? A recent trial, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention study (ATBC), assessed the effects of supplemental a-tocopherol only, P-carotene only, a-tocopherol plus P-carotene, or placebo on the incidence and death from lung and other cancers among 29,133 male smokers aged 50-69. After a median of 6 years of follow-up, this randomized, placebo-controlled clinical trial revealed that lung cancer risk and mortality increased among those who received P-carotene. Prostate cancer incidence decreased among those receiving a-tocopherol. However, both the beneficial and adverse effects of supplementation disappeared during postintervention follow-up. The Finnish researchers indicated that the preventive effects of a-tocopherol on prostate cancer requires confirmation, and that smokers should avoid P-carotene supplements [ 27 ].

A team of investigators from Denmark, Serbia/Montenegro, and Italy sought to determine whether antioxidant supplements prevented gastrointestinal cancers. They identified 14 randomized trials (the "gold standard" of epidemiologic studies), which included 170,525 men and women. Their systematic review found that P-carotene, vitamin A, vitamin C, and vitamin E supplements alone or in combination, had no effect on the prevention of gastrointestinal cancers. But most disconcerting was their finding that these supplements "seem to increase overall mortality" None of the supplements protected against esophageal, gastric, colorectal, or pancreatic cancer [28].

In yet another metaanalysis using the Cochrane Controlled Trials Registry and Medline, this one from the Oregon Health and Science University, Portland, the researchers addressed the issue as to whether supplementation with vitamins A, C, and E; P -carotene; or a multivitamin reduce cardiovascular death, all-causes mortality, or cardiovascular events in the general adult population. After reviewing over 40 studies, they found that randomized controlled trials of specific supplements failed to demonstrate a consistent or significant effect of any single vitamin or combination of vitamins on the incidence of or death from cardiovascular disease [29].

A metaanalysis of randomized controlled clinical trials of nonvertebral fracture prevention with vitamin D supplementation was conducted by a group from the Harvard University School of Public Health and Boston University School of Dental Medicine. They began with the idea that "given the high prevalence, severity and cost of osteoporotic fractures, prevention strategies that are effective, low cost, and well tolerated are needed." Their 12 randomized control trials included 9294 men and women with hip fracture and 9820 for nonvertebral fracture risk. They found that an oral vitamin D dose of 400 IU per day (IU/d) was not sufficient for fracture prevention, but that 700-800 IU/d appeared "to reduce the risk of hip and any non-vertebral fractures in ambulatory and institutionalized elderly persons" [30].

This overview of what can reasonably be considered the optimum studies currently available reveals generally disappointing results for the efficacy of fruits and vegetables to accomplish what was expected of them by way of chronic diseases. The new prospective cohort studies and randomized clinical trials not only do not support the results of observational case-control studies; they contradict them. Also, given the fact that both the prospective studies and clinical trials are far more definitive and reliable, we are compelled to consider them seriously and favorably—-hat fruits, but not vegetables, may provide some small benefit in reducing risks of heart disease. But neither fruit nor vegetables appear to mitigate cancer risks. The idea of "five a day" for better health may have stalled in front of an insurmountable obstacle on the pathway to better health.

This is not the way it was supposed to be. In one of the most widely quoted and respected publications, "Oxidants, antioxidants, and the degenerative

"The Miracle Be rry"

"The Miracle Be rry"

Prevention Magazine June '99

The Blueberry is Ranked #1 out of 40 fruits and vegetables

* Anti-Oxidant Power

* Urinary Tract Health

* Reduce Eye Strain and Fatigue

Figure 4.3. Marketing of blueberries with the benediction of university research.

diseases of aging," Professor Bruce Ames, the lead author, contended that dietary fruits and vegetables are the principal source of ascorbate and carote-noids and are one source of tocopherol. He states: "Low dietary intake of fruits and vegetables doubles the risk of most types of cancer as compared to high intake and also markedly increases the risk of heart disease and cataracts. Since only 9% of Americans eat the recommended five servings of fruits and vegetables per day, the opportunity for improving health by improving diet is great " [ 31 ].

That has been the canon, the dogma, for a quarter of a century. Fruits and vegetables were to be the clear path to health, based primarily on biochemical studies and case-control epidemiologic studies. These new prospective studies and clinical trials will not go down easily.

Nevertheless, if anything has been evident, it is that the advertising and marketing of antioxidant vitamins has been excessive, and that the hype (hyperbole), the claims of benefit for antioxidant -filled food, has obtained ludicrous proportions. What a surprise it was to pick up a container of the most wonderful New Jersey blueberries and read the label, shown in Figure 4.3, and learn that in addition to their luscious taste, Tufts University Research has

The Blueberry is Ranked #1 out of 40 fruits and vegetables

* Anti-Oxidant Power

* Urinary Tract Health

* Reduce Eye Strain and Fatigue

Figure 4.3. Marketing of blueberries with the benediction of university research.

found blueberries beneficial for their antioxidant power, urinary tract health, reduction of eye strain and fatigue, and reduction of buildup of "bad" cholesterol. In their search for an edge, the berry producers use whatever is available.

And what are we to do about the "French paradox," which holds that the antioxidant polyphenols in red wine are protective, allowing the French to eat boldly of fatty cheeses and buttery sauces and have less heart disease than Americans? Or the "Japanese paradox," based on soy and green tea, and the Mediterranean diet heavy on olive oil? Is there any strong evidence for any of these?

The oxidant/antioxidant story is far from over; questions persist. For example, is there no limit to the amount of antioxidant we can use or need? Does anyone know the essential level of antioxidants that we humans require, if there is one? Is there an optimum level? Does it vary weekly, monthly, or yearly, and require checking? Can a healthy individual benefit from additional amounts of antioxidants? Is a person's antioxidant level a measure of health? I'd certainly like to see these questions answered before throwing out the baby with the bathwater. Haste in eliminating vegetables from the diet is uncalled for as new research indicates other beneficial effects. Vegetables are the main dietary source of nitrate (NOs3S , which accounts for 60-80% of our daily nitrate intake. This new research indicates that the previous view that dietary nitrate has only harmful effects requires reconsideration. For example, in the stomach's acidic environment, following a meal with high nitrate concentration (lettuce), the levels of nitrate and nitrite increase markedly, killing most enteric pathogens within an hour, as well as increasing gastric mucosal blood flow [ 32 ].

Having raised questions and concerns about the future of antioxidants, it is now necessary to raise yet another question that brings the entire question of oxidant cell damage and consequent aging into sharper focus.

A newly published study appears to call into question the longstanding and widely held belief that reactive oxygen species are important in the aging process. The new claim is that apoptosis, programmed cell death, which selectively eliminate cells with damaged DNA, not oxidative damage from free radicals, drives the aging and degenerative disease process. This is the work of 18 investigators from five American universities: Wisconsin, Florida, Brown, Vanderbilt, and Texas, along with the University of Tokyo.

These researchers found that mice accumulating mtDNA mutations display features of accelerated aging, and that such accumulation was not associated with oxidative stress. They conclude by stating that "accumulation of mtDNA (mitochondrial) mutations that promote apoptosis may be a central mechanism driving mammalian aging" [33]. This will not be received lightly. We can expect a flurry of new research to either support or refute this new paradigm. But that is what science is all about. We do need to know. If found to be true, we may be a step closer to the fountain of youth. Is that something to look forward to, or is it another one of Pandora's boxes?

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Berry Boosters

Berry Boosters

Acai, Maqui And Many Other Popular Berries That Will Change Your Life And Health. Berries have been demonstrated to be some of the healthiest foods on the planet. Each month or so it seems fresh research is being brought out and new berries are being exposed and analyzed for their health giving attributes.

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