LINUS PAULING INSTITUTE RESEARCH REPORT

Diet and Optimum Health Conference

LPI held its 3rd Diet and Optimum Health Conference on May 18-21 in Portland, Oregon, co-sponsored by the Oxygen Club of California and Oregon Health & Science University. The conference featured 30 speakers from around the world and was divided into seven sessions: Exercise and Health; Lifestyle and Genetic Influences on Bone Health; Antioxidants: Do They or Do They Not Provide Health Benefits?; Bioavailability, Metabolism, and Health Benefits of Flavonoids; Metal Chelators for Disease Prevention and Treatment; Alcohol: Benefits and Risks, and a public session with a panel discussion of the new U.S. Food Guide Pyramid by leading experts. Please contact LPI if you would like to purchase a collection of the scientific abstracts.

The conference opened on Wednesday evening with the presentation of the Linus Pauling Institute Prize for Health Research to Dr. Paul Talalay of Johns Hopkins University, followed by his plenary lecture,“Protection against cancer: Enzyme inducers suppress oxidant, electrophile, and inflammatory damage.” Dr. Talalay noted that the mortality from cardiovascular disease has decreased in the last 25 years, but the incidence of cancer and Alzheimer’s disease is expected to double by 2030 as the percentage of the elderly in the American population increases. Cancer is characterized by a number of molecular events, including the activation of proto-oncogenes, the inactivation of tumor suppressor genes, and the disturbance of cell-signaling pathways and apoptosis, or programmed cell death, that afford multiple opportunities for intervention. Dr. Talalay has focused on the induction of phase 2 enzymes in the liver that suppress inflammation and protect against the toxic and neoplastic effects of electrophiles, which are chemicals that damage DNA by stealing electrons. He discussed the use of the food additives BHA and BHT as cancer chemoprotectants. Both chemicals induce phase 2 enzymes and decrease the incidence, multiplicity, and growth rate of carcinogen-induced tumors in rodents. In addition to its induction of phase 2 enzymes, BHA increases glutathione, an endogenous cellular antioxidant that helps protect against oxidative damage. Dr. Talalay found that vegetables of the Cruciferae family, such as broccoli and Brussels sprouts, contain phytochemicals that are potent inducers of phase 2 enzymes. One such phytochemical, sulforaphane, also increases glutathione levels,thereby protecting against oxidative stress, and induces apoptosis in cultured human cancer cells. Sulforaphane,which is found in especially high levels in broccoli sprouts,also protects the retina from UV light damage and, when applied topically to mouse skin, cuts the incidence of malignant skin tumors and tumor volume by half.

At the banquet on Friday evening, Dr. John Sowell of LPI was honored by the Oxygen Club of California for the most outstanding scientific poster, which presented information on the ascorbylation of lipid peroxidation products (see the Spring/Summer 2005 LPI Research Report for more on how vitamin C renders oxidized lipids harmless). LPI graduate student Hao Wei was recognized for his poster on the toxicity of clioquinol—an antibiotic used in Alzheimer’s disease—when combined with transition metals like copper and iron. Dr. Linus Pauling Jr. and Richard Hicks were inducted into the newly established Linus Pauling Institute Society as its first two members and honored for their extraordinary vision, commitment, and generosity to LPI. Dr. Pauling Jr. served on the Board of Trustees of the Linus Pauling Institute of Science and Medicine since its founding in 1973 and later as its Chairman. Mr. Hicks served as the Executive Vice President of the Linus Pauling Institute of Science and Medicine for nearly 20 years and joined its Board after his retirement.

Dr. John Sowell (right)	Hao Wei (right)	Richard Hicks (left) and Dr. Linus Pauling, Jr. (right)

Exercise and health

Chaired by Dr. Tammy Bray (Oregon State University)

Dr. George Brooks (University of California-Berkeley) discussed the relationships between physical activity, body weight, and protection against chronic diseases. People with a body mass index over 25 kg/m² have an increased risk for chronic disease. Daily physical activity—not limited to exercise—is necessary to balance energy intake and expenditure. Experiments show that this can be achieved with an hour of brisk walking. For those who desire to lose weight, 90 minutes of brisk walking per day is required. Exercise reduces body fat, sustains bone health, increases antioxidant mechanisms, improves blood lipid profiles, and promotes “joie de vie.” Cardiac damage caused by ischemia-reperfusion is a major cause of mortality associated with coronary artery disease. Dr. Scott Powers (University of Florida) suggested that even short-term exercise of three days is cordierite, probably by boosting endogenous anti-oxidants and preventing apoptosis (programmed cell death) in cardiac cells. Feeding an antioxidant-enriched diet to animals resulted in about the same magnitude of circumrotation as exercise, prompting the initiation of human studies. Dr. Frank Booth (University of Missouri) suggested that we are evolutionarily maladapted to our present diet. Genes were selected to support physical activity, but contemporary sedentary lifestyles result in improper insulin sensitivity. As little as three days of inactivity can produce a loss of insulin sensitivity, resulting in hyperlinks and hyperglycemia. Physical inactivity also exacerbates metabolic syndrome, whereas exercise protects against diabetes and enhances immune function.

Lifestyle and genetic influences on bone health

Chaired by Dr. Russ Turner (Oregon State University)

Dr. Connie Weaver (Purdue) discussed optimum calcium intake for bone health and weight control. She presented evidence that insufficient calcium intake in adolescence adversely affects bone mineral density in adults and that children need about 1,300 mg/day of calcium to ensure a good functional reserve of bone calcium. Calcium alone, but not vitamin D alone, protects against low bone mineral density. Epidemiological studies have found an inverse relationship between weight and calcium intake, but the data are insufficient to make specific recommendations for weight loss. Dr. Michael Holick (Boston University) discussed widespread vitamin D deficiency caused primarily by avoiding sun exposure. About 80-100% of our vitamin D is synthesized in the skin; few foods significantly contribute to vitamin D status. In winter in northern latitudes like Boston, virtually no vitamin D is synthesized in the skin. Topical sunscreens in summer decrease the amount of synthesized vitamin D by more than 95%. Inadequate vitamin D is associated with stemmata, osteoporosis, and increased risk for cancer of the colon, prostate, breast, and ovary. According to Dr. Robert Klein (Oregon Health & Science University), animal studies have found that genes influence bone health. One gene in mice and humans that codes for a lipoxygenase—an enzyme that converts polyunsaturated fatty acids into eicosanoids (prostaglandins and other molecules involved in inflammation and other cellular processes)—has been found to affect skeletal development in mice. Variations in this gene are associated with about 3% of the variations in bone mineral density among humans. A high intake of omega-3 fatty acids is associated with increased bone mineral density and a decreased risk for osteoporosis.

Antioxidants: do they or do they not provide health benefits?

Chaired by Dr. Jeffrey Blumberg (Tufts) and Dr. Norman Krinsky (Tufts)

Dr. Norman Krinsky opened the session with a short discussion of the conflicting and often disappointing results of intervention trials with vitamin E and beta-carotene, concluding, “the data are the data” and have to be reckoned with. Dr. Simin Meydani (Tufts) presented the results of studies showing that vitamin E improves immune response in old mice. Vitamin E enhanced synapse formation, inter-leukin-2 production, and T-cell proliferation, and decreased prostaglandin E2, an inflammatory molecule. A study in 451 elderly humans found that 200 IU/day of supplemental synthetic vitamin E for one year decreased the incidence of upper respiratory infections, including the common cold, by 35%. Such a strategy, if widely implemented, may prevent nine million upper respiratory infections in the elderly each year. LPI’s own Dr. Maret Traber reviewed studies on the antioxidant effect of vitamin E in ultra marathon runners and smokers. Levels of F2-isoprostanes (markers of lipid oxidation) doubled in runners given placebos, but were not significantly changed from baseline in runners supplemented with 1,000 mg of vitamin C and 400 IU of natural vitamin E. However, antioxidants did not affect inflammation. In another study, vitamin E disappeared from plasma faster in smokers than in nonsmokers, and even faster in smokers with low levels of plasma vitamin C. Observations on the amount of the vitamin C conjugate formed from reactions with lipid peroxidation products suggested that these conjugates may be markers of vitamin E activity. Dr. Roland Stocker (University of New South Wales, Australia) discussed problems with the lipid oxidation theory of arteriosclerosis, noting that, contrary to early expectations, supplemental vitamin E has not been shown to have much effect in prospective studies. Protocol, synthetic antioxidant, has been found to inhibit arteriosclerosis in animals by preventing macrophage accumulation and smooth muscle cell proliferation. Protocol has anti-inflammatory properties and also promotes endothelial cell growth. It has a site-specific effect that is not associated with the arterial content of oxidized lipids, suggesting that the prevention of lipid oxidation may be less important in arteriosclerosis than commonly believed. Additionally, Protocol loses these functions when theme oxygenase-1, an enzyme that degrades the iron-containing part of hemoglobin, is inhibited, indicating that chemical effects of Protocol are more important than antioxidant function. Oxidative damage to mitochondria, the organelles in cells responsible for energy production, may result in an increased risk for degenerative disease. Dr. Michael Murphy (Medical Research Council, United Kingdom) discussed the use of MitoQ, an antioxidant derivative of coenzyme Q10, as a therapeutic strategy. MitoQ targets the mitochondria and prevents lipid oxidation, protects mitochondria from oxidative damage, and decreases tissue damage during schema injury. Dr. John Milner (National Cancer Institute) reviewed the effect of fruits and vegetables on genes that influence disease risk. This is difficult to determine precisely due to the daily ingestion of over 25,000 dietary constituents present in fruits and vegetables. Some individual have certain genetic polymorphisms that can explain the variable effect of dietary constituents on disease. Gene-nutrient interactions have been described for selenium, garlic, and green tea, and continued research in nutrigenomics and proteomics will elucidate more relationships. The session concluded with remarks by Dr. Jeffrey Blumberg, who addressed the methodological and statistical problems with published antioxidant intervention trials that suffered from inadequate sampling, poor compliance, insufficient duration, no determination of antioxidant status, wrong dose, inappropriate study populations, and “polypharmacy”—subjects on multiple medications that may interact with antioxidants and influence outcomes.

Bioavailability, metabolism, and health benefits of flavonoids

Chaired by Dr. James Joseph (Tufts) and Dr. Rod Dashwood (LPI)

Dr. Martijn Katan (Wageningen University, The Netherlands) reviewed the roles of plant flavonoids—responsible for the deep colors of fruits and vegetables—to attract pollinators, protect against UV damage, repel predators, and inhibit fungi. There are over 7,000 flavonoids, including catechins (tea), anthocyanidins (berries), isoflavones (soy), and flavonols like quercetin (apples). In the 1970s these phytochemicals were suspected mutagens, but animal experiments in the 1980s reported anticancer effects. By the 1990s, flavonoids were found to have antioxidant and antiplatelet effects in vitro. Subsequent research has reported conflicting results, probably because flavonoids in vivo are extensively metabolized—converted into a wide range of other substances—and don’t reach the in vitro experimental concentrations because of poor bioavailability. Dr. Alan Crozier (University of Glasgow, United Kingdom) discussed the absorption and metabolism of flavonoids from tea and onions. Quercetin, an onion flavonol, is extensively and rapidly metabolized—peaking in plasma within an hour after ingestion and largely gone after six hours. Unlike quercetin, which is absorbed in the small intestine, flavonoids from tea are absorbed in the large intestine. Subtle differences in the chemical structure of flavonoids affect the site of absorption, and the food matrix can also influence the degree of absorption. Dr. Francesco Visioli (University of Milan, Italy) discussed the antioxidant effects of olive oil, which is the major source of fat in the Mediterranean diet. Extra virgin olive oil contains flavonoids—absent in more processed oil—that produce flavor. In vitro, olive oil flavonoids modulate enzymes linked to the development of heart disease and cancer. Animal studies have confirmed the antioxidant and antithrombotic effects of olive oil flavonoids, but, except for studies showing decreased oxidative stress and some protection against DNA damage, human data are largely lacking. The green color of some oils is caused by added chlorophyll or carotenoids. Much attention has recently focused on the purported health benefits of chocolate. Dr. Helmut Sies (Heinrich Heine University, Dusseldorf, Germany) explained that cocoa flavonoids, including catechins and procyanidins, have anti-inflammatory functions by inhibiting enzymes involved in the synthesis of inflammatory molecules and by scavenging hydroperoxides. Epicatechin inhibits LDL oxidation and protein damage caused by peroxynitrite. High-flavonoid cocoa improves vasodilation and reduces plasma levels of F2-isoprostanes, which are markers of lipid oxidation. Fifty grams of dark chocolate have antioxidant functions equivalent to six apples, 4 1/2 cups of tea, or seven onions. Dr. Chung S. Yang (Rutgers) discussed the bioavailability of tea flavonoids and their potential prophylaxis against cancer. Tea catechins are absorbed and metabolized differently in mice, rats, and humans. The plasma concentration of one tea catechin, epigallocatechin-3-gallate, reaches its maximum level 60 to 90 minutes after drinking two to three cups of green tea. Its biological half-life is about three to five hours. Tea has been shown to inhibit many types of cancer in animals, but human data lag. While flavonoids may be responsible for the anticancer effect, caffeine also has inhibitory effects. Dr. James Joseph (Tufts) focused on the effects of flavonoids on brain function and aging, which is characterized by a loss in neuronal function and cognitive decline. Oxidative stress and inflammation contribute to these decrements. Feeding blueberries, which contain anthocyanin flavonoids, to rats increases neurogenesis and improves cognitive and motor function. Spinach, strawberries, cranberries, and purple grape juice also improve either cognitive or motor function, depending on the region of the brain to which the specific anthocyanins migrate. Recent experiments suggest that the role of blueberry anthocyanins in cell signaling may be more important than their antioxidant activity.

Metal chelators for disease prevention and treatment

Chaired by Dr. Lester Packer (University of Southern California)

Dr. Des Richardson (Children’s Cancer Institute, Australia) discussed the use of iron chelators in cancer treatment. Cancer cells have a high uptake of and need for iron, and removal of iron can cause cell-cycle arrest and apoptosis (cell death). Novel iron chelators have been developed that can penetrate cell membranes in vitro and bind to and remove iron, resulting in interruptions in the cell cycle and growth inhibition of tumor cells. These novel chelators have been tested in cultured prostate cancer cells and have not exhibited toxicity or unusual side effects at useful doses in animals bearing cells from human tumors. Dr. Silvia Mandel (Technion Institute, Israel) noted that oxidative stress associated with neurodegenerative diseases like Alzheimer’s disease and Parkinson’s disease may be generated by reactive iron ions, which promotepeptide aggregation and neuronal death. Iron chelation may have the potential to reduce oxidative stress implicated in these diseases. Several new iron chelators have been shown to cross the blood-brain barrier and exhibit neuroprotective and neurorescue functions. They also inhibit monoamine oxidase, an enzyme involved in the production of free radicals when iron is present. Dr. George Brewer (University of Michigan) focused on the role of copper chelation in medicine. Excessive copper accumulation causes Wilson’s disease, which is treated with zinc—thereby blocking copper absorption—and tetra-thiomolybdate, which binds with copper and protein, forming a biologically unavailable complex. Angiogenesis, or blood vessel formation, requires copper, and tumors exhibit increased angiogenesis. Tetrathiomolybdate strongly inhibits tumors in mice through its anti-angiogenic effects, and has shown exceptionally promising effects in preliminary trials on advanced and metastatic human cancers. Tetrathiomolybdate also has anti-inflammatory and antifibrotic effects, and human trials on pulmonary fibrosis and billiard cirrhosis are under way.

Alcohol: benefits and risks

Chaired by Dr. Meir Stampfer (Harvard)

Dr. Arthur Klatsky (Kaiser Permanente Medical Center, California) provided a risk-benefit analysis of alcohol consumption. Twelve ounces of beer contain 14 grams of alcohol, equivalent to 4 ounces of wine or 1.25 ounces of whiskey. People who consume three or more drinks per day have a greater risk for cardiomyopathy, hypertension, arrhythmia, and hemorrhagic stroke, although the precise mechanisms involved have not been elucidated. Compared to abstainers and heavy drinkers, light drinkers have a lower risk for heart disease and ischemic stroke. Alcohol increases HDL (the good cholesterol), and wine provides increased protection against heart disease mortality, although there is little difference between red and white wines. Dr. Francois Booyse (University of Alabama-Birmingham) discussed some of the putative mechanisms that may be responsible for the cardio-protective effects of moderate alcohol consumption, in addition to increased HDL. In vitro and in vivo studies with mice have shown that alcohol reduces the deposition of fibrin after fissure of the blood vessel wall, thus inhibiting plaque instability and rupture. This fibrinolytic effect of alcohol would inhibit thrombosis, or clotting, and decrease mortality. Dr. Shumin Zhang (Harvard) discussed the relationship between folate status, alcohol consumption, and cancer risk. Epidemiological studies have identified an increased risk for breast and colon cancers associated with a high intake of alcohol and a low folate status. With inadequate folate, uracil rather than thymine may be incorporated into DNA, resulting in increased risk for mutation. The Nurses’ Health Study found that the risk for breast cancer was increased in those whose intake of folate was less than 150 micrograms/day and whose intake of alcohol was greater than 15 grams/day. Low plasma folate has also been associated with an increased risk for breast cancer. Additionally, genetic polymorphism's in the methylenetetrahydrofolate gene influence cancer susceptibility, and metabolic products of alcohol can degrade this enzyme.

Public session: the U.S. Food Guide Pyramid and what Americans should eat to be healthy

Moderated by David Heil (David Heil & Associates)

David Heil introduced the members of the panel and cited increasingly alarming obesity and exercise statistics as he set the stage for a discussion of the USDA Food Guide Pyramid. Dr. Meir Stampfer (Harvard) criticized the 1992 Food Guide Pyramid for not distinguishing between good and bad fats, types of carbohydrates, and sources of protein, and overemphasizing milk, carbohydrates, and red meat. Additionally, only one study was conducted to learn if adherence to the guidelines actually promoted health, finding that only a small benefit was observed. In contrast, closely following alternative guidelines proposed by the Harvard group that emphasize exercise, whole grains, plant oils, fruits, vegetables, nuts, and legumes was associated with a 40% and 30% reduction in heart disease risk in men and women, respectively, although the effect on cancer was insignificant. Low-fat diets do not sustain weight loss, and a high glycemic diet in overweight people doubles the risk for heart disease compared to lean people. Dr. Stampfer suggested that drinking milk is unnecessary to maintain healthy calcium status, which can be achieved through other foods and supplements. Dr. Janet King (Children’s Hospital Oakland Research Institute, California) reviewed the rationale for the new U.S.Food Guide Pyramid released in January 2005. The dietary guidelines are revised every five years and establish the U.S. nutrition policy for all Americans two years of age and older. Previously, dietary guidelines were written by scientific experts for public dissemination. The recent guidelines were translated from the technical report to produce the public document. Implementation strategies include the Food Guide Pyramid, which emphasizes regular exercise to achieve energy balance and the consumption of nutrient-dense foods that should improve micronutrient status—clearly deficient in many Americans. The old term “serving” has been replaced with “cups” or “ounces” for clarity. Small, incremental changes in one’s habits may be the best strategy for improving dietary and exercise status. The new Food Guide Pyramid has been criticized for not plainly stating what foods to avoid. Dr. Martijn Katan (Wageningen University, The Netherlands) noted that weight loss does not depend on the fat content of the diet, but rather on diet compliance and the difference between caloric intake and expenditure. There is some evidence that a low-fat diet may protect against recurrence of breast cancer, but an understanding of the importance of the type of fat is lacking. Clinical trials have found that replacing saturated and trans fats in the diet with unsaturated fats lowers the risk for heart disease. Trans fats raise LDL (“bad”) and lower HDL (“good”) cholesterol, and an intake of as little as five grams per day of trans fat increases the risk for heart disease by 25%. Although epidemiological studies have found an association between fish consumption and decreased risk for death from heart disease, clinical trials with fish oil containing omega-3 fatty acids have largely failed to support this protective effect. Canola oil contains alpha-linolenic acid and monounsaturated fats, which are poorly converted in the body to omega-3 fatty acids. Tropical oils like palm oil contain as much as 50% saturated fat and are increasingly popular, but we have scant knowledge of their health effects. Dr. Barbara Howard’s (MedStar Research Institute, Maryland) message was to “eat less, move more.” Successful and sustained weight loss is accomplished by incremental changes involving the consumption of fewer calories, increased physical activity, and behavior modification. A good strategy is to eat a balanced diet featuring ample fruits, vegetables, and whole grains, and avoid calorie-dense foods and liquid calories. It is better to strive for modest weight loss of 10% and maintain that for six months before setting a new objective than to try to lose too much weight quickly. Since restaurants tend to serve portions much larger than those consumed at home, dining at home more frequently may also help.

Last updated November, 2005

Micronutrient Research for Optimum Health