LINUS PAULING INSTITUTE RESEARCH REPORT

Diet and Optimum Health Conference

The second "Diet and Optimum Health" conference was convened by the Linus Pauling Institute in Portland, Oregon, on May 21-24, 2003, and featured presentations by 31 experts from around the world. The conference was organized into five sections: brain function and neurodegenerative diseases, aging, cancer, eye diseases, and diabetes. A public session featured a presentation by Dr. Walter Willett, the recipient of the 2003 Linus Pauling Institute Prize for Health Research, as well as talks on cancer, heart disease, obesity, and cognitive function. A packet of complete abstracts of the presentations is available from LPI for $15. Please contact us for more information.

The conference opened with a plenary lecture by Dr. Barry Halliwell of the National University of Singapore, where he is head of the Department of Biochemistry. Dr. Halliwell co-wrote with John Gutteridge the acclaimed textbook Free Radicals in Biology and Medicine and is one of the world's most influential scientists in the fields of free radical biology and biochemistry. Dr. Halliwell discussed the imperative need for valid biomarkers of oxidative damage in the human body. He defined a biomarker as a "measurable parameter that predicts the later development of disease" and listed the attributes of an ideal biomarker as one that is predictive, reliable, and detects the major percentage of oxidative damage. Furthermore, the biomarker should not be confounded by diet or formed artifactually, and its levels should be constant in the same subject at different times. Presently, no biomarker of oxidative damage has been fully validated, although data suggest that existing biomarkers for oxidative DNA and lipid damage may be valuable. Dr. Halliwell illustrated the difficulty in selecting appropriate biomarkers with a discussion of hydrogen peroxide, which is present in urine but not plasma and can be generated artifactually and influenced by diet.

Brain function and neurodegenerative diseases

Dr. Joseph Beckman (LPI) discussed the roles of peroxynitrite and zinc in amyotrophic lateral sclerosis (ALS). Peroxynitrite is a dangerous nitrogen compound formed from the reaction between nitric oxide and the superoxide radical that can damage motor neurons. In ALS patients, a mutation in superoxide dismutase, an enzyme that scavenges superoxide, causes toxicity when coupled with zinc deficiency. Dr. Beckman noted that zinc deficiency in a mouse model of ALS accelerates the progression of the disease and that treating the mice with the appropriate amount of zinc normalized the mortality curve. Dr. Flint Beal (Cornell) described the therapeutic application of coenzyme Q10 in Parkinson's disease. In a 16-month trial, patients supplemented daily with 300 mg or 600 mg of CoQ10 exhibited a 25% decrease in the rate of disease progression, while those patients given 1,200 mg/day of CoQ10 experienced a 44% decrease in the rate of progression. CoQ10 was well tolerated, and studies are currently evaluating the effect of larger doses. The protective effect of dehydroascorbic acid (DHA), the primary oxidation product of ascorbic acid (vitamin C), against stroke in mice was addressed by Dr. David Golde (Memorial Sloan-Kettering). His research showed that DHA, but not ascorbic acid, crosses the blood brain barrier and is then reduced intracellularly to ascorbic acid in brain tissue. Vitamin C also reduced the mutation rate in human cells by about 50%. Dr. Christian Behl (Johannes-Gutenberg-Universitat, Germany) discussed the possible protective role of antioxidants, including vitamin E and estradiol, an ovarian hormone, against Alzheimer's disease and stroke. Vitamin E inhibits the toxicity of a protein called amyloid beta found in the brain of Alzheimer's patients, but its bioavailability in the brain has not yet been verified. Estradiol prevents nerve cell death in vitro and in vivo, based on its antioxidant activity. In the Framingham study, high levels of homocysteine, a product of methionine metabolism, were found to be associated with Alzheimer's disease and loss of cognitive function. Dr. Jacob Selhub (Tufts) discussed the use of folate, vitamin B6, and vitamin B12 to lower homocysteine levels. High homocysteine levels have also been positively correlated with heart disease and stroke. Homocysteine determinants include vitamin intake, genes, age, gender, kidney function, and lifestyle factors. Dr. Ashley Bush (Harvard) claimed that the cause of Alzheimer's disease will eventually be revealed by successful therapy. He noted that the neurotoxicity of amyloid beta is mediated by metal ions like copper, iron, and zinc. Neurotoxicity may be attributable to the generation of hydrogen peroxide by reactions between copper and amyloid beta, and Dr. Bush is investigating the effect of chelating agents that bind copper and may prevent these deleterious reactions in Alzheimer's patients.

Aging

Dr. Dean Jones (Emory) discussed the change in thiol status associated with aging. Thiols are sulfur-containing compounds; one important intracellular thiol antioxidant is glutathione. The ratio of reduced to oxidized glutathione decreases with age, and this redox status may determine cell survival. Perturbations in glutathione redox status are also found in subjects with type 2 diabetes and vascular disease. Caloric restriction is the only successful, non-genetic means to extend lifespan. Dr. Nikki Holbrook (Yale) noted that caloric restriction of 30-40% reduces reactive oxygen species in animals and improves their response to oxidative stress. Long-term caloric restriction provided the greatest benefit, but even short-term caloric restriction in old rats boosted defenses and increased cell survival. These effects may be mediated through the activation of a protein kinase called ERK. Dr. Kelvin Davies (University of Southern California) discussed the role of calcium in cell signaling events following oxidative stress, which causes an increase in intracellular calcium. High calcium levels alter cell signaling, resulting in the activation of genes that encode proteins that protect against oxidants. Chronic expression of these genes that offer short-term protection is, however, associated with pathological changes observed in neurodegenerative diseases. Dr. Christiaan Leeuwenburgh (University of Florida) addressed the age-related effect of caloric restriction on cell signaling. He found that caloric restriction inhibited apoptosis, or programmed cell death, in the brains of old rats. Caloric restriction also improved calcium homeostasis, reduced hydrogen peroxide production, improved brain function in old animals, and reduced both oxidative damage to skeletal muscles and apoptosis in muscle cells. Elderly patients are at greater risk than adults for death following a heart attack. Dr. Charles Hoppel (Case Western Reserve University) speculated that this may be due to cardiac mitochondrial dysfunction in the elderly. He found oxidative damage to cardiolipin, an essential component of the cardiac mitochondrial membrane, only in the hearts of old rats after ischemia, which may also account for the increased mortality in elderly humans following a heart attack. Dr. Edward Lakatta (National Institute on Aging) noted the "normal" changes that occur in the aging heart in healthy humans without heart disease, including diminished cardiac reserve, impaired contractile function, altered calcium status, and increases in the size of the heart and heart cells. Additionally, the artery wall thickens and stiffens. Dr. Lakatta suggested that these changes should be considered as specific risk factors for heart disease and as targets for intervention.

Cancer

Dr. Jay Heinecke (University of Washington) discussed the biochemistry of inflammation and its association with cancer. He noted that myeloperoxidase, an enzyme released by white blood cells (leukocytes) at the site of inflammation, chlorinates uracil to chemically-modified DNA mutagens. The chlorinated compounds do not directly modify DNA; they damage the nucleotides incorporated into DNA. These reactions can be strongly inhibited by vitamin C and glutathione. Dr. Albena Dinkova-Kostova (Johns Hopkins University) highlighted the potential anti- cancer function of dietary constituents that induce Phase 2 enzymes in the liver. Phase 2 enzymes can detoxify DNA-damaging compounds, which are then excreted. Whereas antioxidants act directly by scavenging radicals, inducers of Phase 2 enzymes work indirectly and have longer lasting effects. The most potent inducers of these enzymes are isothiocyanates from cruciferous vegetables, especially sulforaphane in broccoli. Vitamin D, formed in the skin by exposure to sunlight and supplemented in dairy products, may help protect against prostate cancer. Dr. Donna Peehl (Stanford) reviewed the evidence suggestive of this protective function. Vitamin D suppresses proliferation and promotes differentiation of prostate cells. Its synthesis is inhibited by high calcium intake, which may explain the association between high calcium intake and increased risk of prostate cancer. Due to the toxicity of vitamin D in high doses, work is under way to evaluate synthetic analogs, pulsed delivery of vitamin D, and precursors of vitamin D in treating prostate cancer. Dr. George Bailey (LPI) talked about cancer prevention with chlorophyllin, a derivative of the green pigment in plants. Chlorophyllin has been found to inhibit cancer in trout and people exposed to aflatoxin, which is a mold toxin that causes DNA damage, by forming a chemical complex that is excreted. Chlorophyllin also inhibited cancer in trout caused by exposure to heterocyclic amines, or "cooked meat mutagens". However, chlorophyllin given to rats exposed to carcinogens also promoted cancer at some doses. Natural chlorophyll did not enhance cancer. Dr. Gary Stoner (The Ohio State University) evaluated the anticancer effect of strawberries and black raspberries. While it is not known which chemical constituents of berries are chiefly responsible, berries have been shown to inhibit esophageal and colon cancer in rats. Berry extracts exert antioxidant functions and inhibited growth and promoted apoptosis (programmed cell death) in cultured human cancer cells. The prevention of polyps with berries and the bio-availability of berry phytochemicals are presently being evaluated in clinical trials. Dr. Michael Wargovich (University of South Carolina) focused on the prevention of colon cancer with botanical supplements, including gingko biloba, tumeric (curcumin), milk thistle (silymarin), garlic, and ginseng. These herbs contain phytochemicals that may act as non-steroidal anti-inflammatory agents and mediate prostaglandin synthesis, but with fewer side effects and lower toxicity. Ginseng has been found to inhibit the formation of precursors of colon cancer in rats and also kills colon cancer cells in culture.

Eye diseases

Dr. Leo Chylack (Harvard) reported the results of several clinical trials on the use of micronutrients to slow cataract formation. The Roche European American Cataract Trial (REACT) found that supplementation with vitamins C and E and beta-carotene slowed the progression of cataracts, whereas the Age-Related Eye Diseases Study (AREDS), using similar vitamins at lower doses plus zinc and copper, did not find any benefit of supplements. Differences among the study subjects at baseline, additional multivitamin supplementation in AREDS, and early vs. later intervention may account for the disparate results of the trials. Retinitis pigmentosa (RP) is a hereditary eye disease that affects about 1.5 million people in the U.S. Environmental factors influence the progression of RP, which affects rods and cones in the eye, resulting in a loss of visual acuity. Dr. Eliot Berson (Harvard) discussed the results of antioxidant vitamin intervention trials in RP patients. Vitamin A, but not beta-carotene, was found to rescue cones and slow the decline in visual function. Subjects on high-dose vitamin E fared worse than subjects taking placebos after about 3 years. Dr. Max Snodderly (Medical College of Georgia) noted that the macula in the primate eye contains the carotenoids lutein and zeaxanthin, which are piments in yellow fruits and vegetables. Patients with macular degeneration have low amounts of these pigments in the macula. Omega-3 fatty acids interact with these carotenoids, and despite great heterogeneity among people, an adequate intake of fatty acids and carotenoids may reduce the risk of macular degeneration.

Diabetes

Dr. John Baynes (University of South Carolina) referred to humans as "low temperature ovens" in which oxidative and non-oxidative damage to proteins, known as advanced glycation and lipoxidation end-products (AGE and ALE), accumulates with age and may be associated with diabetic complications. Pyridoxamine (PM), which is a form of vitamin B6, decreased the formation of AGE and tri-glyceride levels in non-diabetic rats that are a model of the metabolic disorder, syndrome X. PM also lowered the lipid level in the blood of diabetic rats but had no effect on blood glucose. PM may also inhibit lipid oxidation, which is a source of protein modification. Dr. Tammy Bray (Oregon State University) suggested that genetic, developmental, infectious, environmental, and dietary factors play roles in the development of insulin dependent diabetes (IDDM, also called type I diabetes), and that reactive oxygen species (ROS) may play a central role. ROS trigger gene activation that leads to inflammation and the death of insulin-producing pancreatic cells. In a non-obese diabetic mouse model, an antioxidant cocktail inhibited the adverse gene activation. Human studies also suggest that antioxidants may reduce the susceptibility to IDDM. Dr. Hans Tritschler (Viatris GmbH & Co., Germany) reviewed the clinical trials using alpha-lipoic acid to treat diabetic neuropathy. A meta-analysis of four trials showed that alpha-lipoic acid (600 mg/day) ameliorated neuropathy, pain, and burning sensations without adverse effects. Alpha-lipoic acid normalized endoneural blood flow and the rate of nerve signal transmission in diabetics with polyneuropathy. However, the trials exhibited large variability, so future trials should be designed carefully.

Public session

Dr. Walter Willett (Harvard), recipient of the 2003 Linus Pauling Institute Prize for Health Research, opened the public session with a talk on the relationship between health and diet and behavior. He argued for a revision of the USDA Food Guide Pyramid that currently recommends restricting all dietary fat and consuming large amounts of starch. Metabolic studies and recent epidemiological research, such as the Nurses' Health Study, have revealed that total fat intake is not related to heart disease risk, but saturated fat and trans fat intake is associated with increased risk. Trans fat, listed as "partially hydrogenated vegetable oil" on packaging, depresses levels of the good cholesterol, HDL, and, on a weight basis, is twice as bad as saturated fat. The Mediterranean diet, emphasizing whole grains, fish, vegetables, fruit, and up to 35% of daily calories from fat like olive oil, is beneficial in maintaining weight loss and to patients who have had a heart attack. Weight control and physical activity also reduce the risk for type 2 diabetes and cancer. Dr. Willett speculated that the incidence of major chronic diseases could be dramatically reduced by selecting proper dietary fats and whole grains, fish, poultry, nuts, and legumes as protein sources. Dr. Lenore Arab (University of North Carolina) estimated that 300 million cases worldwide of cancer each year may be preventable. Strong evidence indicates that colon, rectal, and stomach cancer may be preventable by dietary modifications. Dr. Arab reviewed the putative protective substances in food, including ellagic acid in berries (highest in less ripe berries), catechins in tea, and lycopene in tomatoes. Additionally, evidence of cancer chemo-prevention exists for substances in citrus peel, garlic, cruciferous vegetables, and spices. Beta-carotene from food—but not from supplements—is associated with a reduced risk of cancer. Angiogenesis (new blood vessel growth) in tumors may be inhibited by flavonoids and promoted by macronutrients, such as carbohydrate and fat. Dr. David Heber (University of California-Los Angeles) presented preliminary evaluations of the anticancer effect of certain botanicals and supplements, including Chinese red yeast rice, green tea, and several Chinese herbs. Chinese red yeast rice is a fermented product of white rice that lowers cholesterol in hypercholesterolemic subjects and is being investigated for anticancer functions in cell culture and animal experiments. Various polyphenols in green tea, such as epigallocatechin gallate, protect DNA and can inhibit tumor growth, metastatic capacity, and angiogenesis. Dr. Penny Kris-Etherton (The Pennsylvania State University) explained the modifiable risk factors for heart disease, noting that cholesterol levels can be decreased by a diet low in saturated fat and high in fiber. The so-called DASH diet, which is abundant in fruits and vegetables and features low-fat dairy products, can reduce blood pressure in two weeks. Several studies have found that a diet rich in omega-3 fatty acids from fish and plants helps prevent secondary clinical events in heart disease patients. For example, a recent study found that consuming 200-400 grams of fish per week reduced mortality in heart disease patients by 30%. Additionally, eating legumes four times per week and nuts three times per week reduces the risk of heart disease. Dr. John Foreyt (Baylor) addressed the issue of obesity, which is rapidly becoming more prevalent in the United States. In 1980, 46% of Americans were overweight. By 2000, 65% of Americans were overweight, with a body mass index of more than 25 kg/mg² and at least 15 pounds over an ideal weight. Dr. Foreyt listed three strategies for weight control: 1) a food diary, 2) measurements of food quantity, and 3) an activity record. Small changes can bring incremental benefits, and it is important to set realistic goals in the context of stress management and social support. The balance between caloric intake and expenditure can be partly normalized with at least one hour of exercise every day. Dr. Jim Joseph (Tufts) discussed the importance of pigmented substances in fruit in protecting the brain during aging. The brain is very sensitive to oxidative stress, and antioxidants may be expected to counteract the deleterious effects of oxidants that promote inflammation. In animal tests of cognitive performance, supplemental blueberries and cranberries produced the greatest benefit. Blueberries and strawberries protected against radiation-induced damage. Enhanced performance even in young rats was observed with blueberries. These fruits rank high in an assay that measures their ability to quench free radicals, suggesting that amelioration of oxidative stress in older animals may account for the cognitive benefits.

The bottom line

Once again, the importance of dietary factors and lifestyle in preventing disease was emphasized with discussions of biochemical and epidemiological research.

Oxidative stress is associated with aging, and caloric restriction, which experimentally prolongs the lifespan in animals, may exert a beneficial effect, in part, by decreasing oxidative stress. The amelioration of oxidative stress—caused, for example, by inflammation—may also provide benefits to patients with diabetes, heart disease, cancer, or neurodegenerative diseases.

Certain fruits and vegetables and extracts from these foods contain phytochemicals that have been found to inhibit cancer and improve cognitive performance in animals. For example, sulforaphane in broccoli and broccoli sprouts, the chlorophyll derivative chlorophyllin, strawberries, black raspberries, and certain botanicals inhibit cancer in cell culture, animal, or human studies. Blueberries, cranberries, and strawberries improve cognitive performance in rats, an effect that may be related to the berries' antioxidant function.

A number of speakers suggested that there is some utility in treating certain diseases with specific micronutrients. For instance, alpha-lipoic acid ameliorates the poly-neuropathy associated with diabetes. Large doses of coenzyme Q10 have been shown to slow the rate of progression of Parkinson's disease in preliminary trials. Chemicals related to vitamin D may be valuable in treating prostate cancer. Additionally, vitamin A slows the decline in visual acuity associated with retinitis pigmentosa, and in some populations supplemental vitamins C and E and beta-carotene may slow the progression of cataracts.

An outdated Food Pyramid may be leading people to select foods that do not promote optimal health and, when combined with excessive caloric intake and insufficient exercise, contributes to the obesity problem in the U.S. Good health and protection from heart disease, the leading cause of death among Americans, will accrue from a judicious intake of proper dietary fats, such as omega-3 fats from fish and mono- and polyunsaturated fats from plant oils, whole grains, fruit and vegetables, and legumes and nuts. Trans fat, also known as partially hydrogenated vegetable oil or vegetable shortening, should be eliminated because it reduces "good" (HDL) and increases the "bad" (LDL) forms of cholesterol, and saturated fats should be used sparingly. Following this dietary advice, coupled with ample physical activity, could substantially improve our health and longevity.

Last updated November, 2003

Micronutrient Research for Optimum Health