Diet and Optimum Health Conference
"Diet and Optimum Health", an international conference convened by the Linus Pauling Institute in Portland, Oregon, on May 16-19, 2001, featured 32 experts from around the world who gave up-to-date presentations on the role of nutrition in health. The conference, one of many events to honor Linus Pauling during the hundredth anniversary of his birth, was divided into four sections: diet and cancer, with sessions on causes and prevention and therapy; diet and cardiovascular diseases, with sessions on causes and risk factors and prevention and treatment; diet, neurodegenerative diseases, and aging, with sessions on aging and longevity and cognitive function and neurodegenerative diseases; and a public session. This article summarizes the conference highlights.
The conference opened with the plenary lecture by Dr. Takashi Sugimura, President emeritus of the National Cancer Center in Japan. Dr. Sugimura related his discovery of the heterocyclic amines (HCA), or cooked-meat mutagens. He observed the smoke from sardines cooking in his kitchen and speculated that it, like cigarette smoke, may contain carcinogens. Laboratory tests confirmed his suspicion and stimulated an enormous amount of research on HCA found in meat, fish, and poultry cooked at high temperatures. Dr. Sugimura noted that epidemiological studies do not consistently support a role for HCA in human cancer and that other factors, such as gastric bacterial infection and inflammation, combined with HCA exposure may have a more pronounced carcinogenic effect.
On Thursday evening, Tom Hager, author of the celebrated biography Force of Nature: The Life of Linus Pauling, gave a fascinating lecture on Linus Pauling's progression from molecular to orthomolecular medicine. Early in his career, Pauling applied techniques he learned in Germany while studying quantum physics to solve the structure of inorganic substances. As his interest in biological molecules deepened, he turned his attention to protein molecules and discovered the alpha-helix structure, a fundamental structural theme of proteins. He studied hemoglobin and, in an astounding burst of creative insight, discovered the cause of sickle-cell anemia, the first disease to be characterized as a molecular disease.
Throughout his career Linus Pauling suffered from severe colds that were often noted in his research notebooks. When alerted to the possible value of vitamin C in preventing colds in the mid-1960s, he found, to his immense relief, that he was able to almost completely prevent them by taking supplemental vitamin C. He studied the medical literature and published a meta-analysis of the clinical trials of vitamin C and the common cold in 1970, which quickly became a popular and influential book. Subsequent clinical trials have validated the efficacy of large doses of vitamin C in ameliorating symptoms and shortening the duration of colds. Pauling codified nutritional medicine in his 1968 paper "Orthomolecular Psychiatry" and continued research on the role of vitamin C in preventing and treating cancer, heart disease, and other illnesses until his death in 1994.
Diet and Cancer
Causes and Prevention, chaired by Dr. George Bailey (Oregon State University) and Dr. David Williams (LPI)
Dr. Laurence Kolonel (University of Hawaii) reviewed the epidemiological evidence that associates increased or decreased risk for cancer with diet. He noted that a high intake of meat, salted fish, high-fat dairy products, or alcohol correlates with increased risk of various cancers and that ample fruits, vegetables, and, possibly, legumes offer significant protection. Protective factors include vitamins, selenium, and phytochemicals like carotenoids and flavonoids. Energy balance may be a more important risk factor than simple obesity, and physical activity has consistently been reported to help prevent colon cancer and, to a lesser extent, breast cancer. • Dr. Diane Birt (Iowa State University) addressed the interactions between hormones (e.g. glucocorticoid hormones, including cortisol in humans and corticosterone in rats, and insulin-like growth factor) and dietary energy restriction (DER) in cancer chemoprevention. Obesity and inactivity account for a substantial percentage of various cancers in humans, while DER and sufficiency of certain hormones inhibit cancer in animal models. • Dr. Steffen Loft (University of Copenhagen) argued for the use of mechanistically based biomarkers to assess oxidative DNA damage in order to explore the relationship between dietary factors, including antioxidant vitamins, and cancer. There is little evidence that fruits and vegetables per se exert direct antioxidant effects on DNA. For example, several studies have shown that neither a controlled fruit and vegetable diet nor antioxidant vitamin supplementation in humans affected markers of DNA damage in urine. • Dr. John Potter (Fred Hutchinson Cancer Research Center) discussed the cause and prevention of colorectal cancer. Physical activity and a high intake of vegetables supplying adequate folate help prevent colorectal cancer, while high meat and alcohol consumption, a family history of colorectal cancer, and smoking increase the risk. • Dr. Rod Dashwood (LPI) focused on diet-gene interactions important in the protection against colon cancer and liver cancer in rats by tea constituents and chlorophyll, respectively. White tea offered the greatest protection against cooked-meat mutagens in both bacterial assays and in the aberrant crypt focus (a precursor of colon cancer) assay in rats. Chlorophyllin, a water-soluble derivative of chlorophyll, blocks the body's uptake of cooked-meat mutagens (HCA) and, like tea constituents, affects the expression of genes that regulate cell cycle and induce programmed cell death. • The function of certain phytochemicals, such as isothiocyanates (e.g. sulforaphane in broccoli), in inducing phase 2 liver enzymes that detoxify or metabolize carcinogens and toxins was highlighted by Dr. Tom Kensler (Johns Hopkins University). The monitoring of enzyme induction has resulted in the development of phytochemicals like sulforaphane and the synthetic drug oltipraz, whose chemical structure resembles that of a phytochemical, as chemopreventive agents.
Cancer Therapy, chaired by Dr. Gladys Block (University of California-Berkeley)
Dr. Michael Gould (University of Wisconsin-Madison) continued the theme of cancer chemoprevention by vegetables and fruits, especially chemicals called mono-terpenes from citrus peel. By weight, 95% of the oil in an orange peel is a monoterpene called limonene, which is now being evaluated as a cancer therapeutic agent in the initial phase of a clinical trial. Based on positive results as a chemo-preventive and therapeutic agent in animals, another monoterpeneperillyl alcoholhas shown promising results in treating human cancer and is also being assessed in the initial phase of a clinical trial. • Dr. Steven Clinton (Ohio State University) reviewed the role of saturated fats, red meat consumption, excess caloric intake, and, possibly, excess calcium (more than 2,000 mg/day) in prostate cancer risk and the factors that may help prevent prostate cancer, such as lycopene in tomatoes, cruciferous vegetables, vitamin E, soy, selenium, and omega-3 fatty acids. • Dr. Kedar Prasad (University of Colorado) discussed the biochemical rationale for the use of vitamins C and E combined with standard cancer chemotherapy or radiation, which has resulted in striking tumor cell cytotoxicity in vitro. Some clinical data support this strategy. For example, lung cancer patients who got vitamins C and E and beta-carotene in addition to standard chemotherapy had a better response than those who got only chemotherapy.
Diet and Cardiovascular Diseases (CVD)
CVD Causes and Risk Factors, chaired by Dr. Helmut Sies (Heinrich Heine University)
Heart disease is the leading cause of mortality in the United States and may be substantially reduced by not smoking and by lowering cholesterol levels, according to Dr. Ernst Schaefer (Tufts). Other risk factors include elevated lipoprotein(a) and homocysteine levels and genetic predisposition. While antioxidant vitamin trials have not impressively lessened clinical outcomes in CVD patients, restriction of dietary saturated fats and replacement with unsaturated fats have reduced the risk for CVD. • Dr. Walter Willett (Harvard) advocated the elimination of trans fats, also called partially hydrogenated vegetable oil or vegetable shortening, from the diet in order to avoid their adverse effects on blood lipids. Trans fats not only increase LDL ("bad") cholesterol, triglyceride, and lipoprotein(a) levels, but also decrease HDL ("good") cholesterol levels, resulting in an increased risk for CVD. The effect of trans fats on LDL/HDL ratios is about twice as bad as that of saturated fats. Trans fats also negatively affect blood vessel function and insulin resistance. Replacing trans fats with mono- and polyunsaturated fats, including omega-3 fatty acids; choosing whole grain foods, ample fruits and vegetables; and food fortification with folic acid may substantially reduce the risk for CVD. • Dr. Roland Stocker (Heart Research Institute, Australia) offered the provocative view that while oxidative stress is implicated in CVD, oxidation of lipids may not be the cause of atherosclerosis. Based on animal and other studies, he suggested that lipid oxidation is not directly associated with atherosclerosis. Instead, oxidation of the protein moeity of LDL cholesterol may be more important for atherosclerosis.
CVD Prevention and Treatment by Diet and Supplements, chaired by Dr. Maret Traber (LPI) and Dr. Enrique Cadenas (University of Southern California)
Dr. Frank Hu (Harvard) discussed the role of fruits and vegetables in reducing the risk for stroke, hypertension, and heart attack. The consumption of whole grains; alpha-linolenic acid, an omega-3 fatty acid found in soybean and canola oil; and nuts reduces the risk for CVD. Whole grains may lower CVD risk by exerting a favorable effect on glycemic index, which is a measure of blood glucose levels after a meal. The consumption of nuts reduces cholesterol levels and enhances the generation of nitric oxide, which normalizes vascular function. • Dr. René Malinow's (Oregon Health & Science University) presentation focused on reducing CVD risk by lowering plasma homocysteine levels with folic acid, although the modulation of plasma homocysteine levels by folate supplementation has been observed to be quite variable among individuals. Homocysteine has emerged as a significant independent risk factor for CVD and for non-CVD mortality. • Dr. J. Michael Gaziano (Harvard) underscored the need for well-designed, controlled, randomized trials with antioxidants to determine their value in preventing and/or treating heart disease because most of the completed studies have given equivocal results, possibly due to large variations in dose, duration, and form of the antioxidant tested. He also emphasized that future trials should use combinations of antioxidants. • Dr. Kenny Jialal (University of Texas Southwestern Medical Center) highlighted the role of inflammation in atherosclerosis. In addition to its antioxidant effect, vitamin E is anti-inflammatory at doses greater than 800 IU/day and exerts anti-atherogenic effects. Vitamin E decreases C-reactive protein, which is a biomarker for inflammation and predictive of cardiovascular events. • Dr. John Keaney Jr. (Boston University) focused on another valuable function of vitamin E in decreasing platelet aggregation. Nitric oxide (NO) has been shown to regulate arterial relaxation, which normalizes blood flow. Platelets make NO, but this activity diminishes as they aggregate. Vitamin E enhances NO function by preventing platelet aggregation and by inhibiting the formation of the oxygen radical superoxide. It is known that superoxide can interfere with NO vascular function by reacting with it to form peroxynitrite, a reactive nitrogen species that damages biomolecules. • Dr. Joseph Vita (Boston University) continued the discussion of the ability of antioxidants to normalize vascular function. He presented the results of clinicaltrials that found improved vascular function in coronary artery disease patients 2 hours after an oral dose of 2,000 mg of vitamin C or 15 ounces of black tea and after 4 weeks of treatment with 500 mg of vitamin C or 30 ounces of black tea daily. Vascular dysfunction is associated with cardiovascular events like stroke and heart attack.
Diet, Neurodegenerative Diseases, and Aging
Aging and Longevity, chaired by Dr. Donald Reed (Oregon State University)
Dr. Richard Weindruch (University of Wisconsin-Madison) noted that caloric restriction is, so far, the only strategy that extends lifespan in mammals. Caloric restriction improves many physiological parameters and may retard aging and lengthen lifespan by reducing free radical damage. Even when implemented in mid-adulthood in mice, caloric restriction can extend lifespan by 10 to 20%. • Dr. Tory Hagen (LPI) presented his research on mitochondrial dysfunction, which is associated with aging in rats. With age, mitochondria become more susceptible to oxidative damage, partly because their levels of protective vitamin C and glutathione decrease. Supplementation of rats with two "age-essential" micronutrients, L-carnitine (a non-protein amino acid) and R-lipoic acid, significantly improves mitochondrial function. L-carnitine improves the conversion of fatty acids to ATP, which is the cell's chemical form of energy, and lipoic acid reverses the age-related decline of glutathione, an intracellular antioxidant, in cells and mitochondria. Vitamin C loss in the cells of old rats can also be reversed by supplementation. • The brain is especially vulnerable to oxidative stress because it consumes about 20% of the oxygen used by the body. Therefore, the consumption of fruits and vegetables that contain antioxidant substances may slow brain aging and protect against neurodegenerative diseases like Alzheimer's disease, according to Dr. Jim Joseph (Tufts). He showed that anti-oxidant and anti-inflammatory extracts from blueberries called anthocyanins fed to mice substantially improved their performance in a water maze test of cognitive function. Antioxidant-rich spinach extracts had a similar effect.
Cognitive Function and Neurodegenerative Diseases, chaired by Dr. Joseph Beckman (LPI)
Dr. Barry Oken (Oregon Health & Science University) reviewed the complementary/alternative therapies for Alzheimer's disease. Perhaps due to the lack of standardization of gingko biloba preparations and variability in dose, the results of clinical trials to assess its impact on cognitive function and behavior have had variable outcomes. Lack of standardization, misidentification, adulteration, and contamination also plague the clinical evaluation of other phytochemicals and botanicals. A trial of 2,000 IU/day vitamin E in Alzheimer's disease patients showed no improvement in cognitive performance, although the time to placement in nursing homes was delayed. • Oxidative damage is a hallmark of the aged brain and is especially elevated in the brains of Alzheimer's disease patients. Dr. Elizabeth Head (University of California-Irvine) presented data from canine studies showing that the consumption of a diet rich in antioxidants, including vitamin C, improves cognitive function and complex learning in old dogs but has little effect in young dogs. Senile dogs share many of the same pathophysiological features of dementia with Alzheimer's patients. • Dr. Mark Smith (Case Western Reserve University) introduced the observation that Alzheimer's disease patients consume about 400 more calories daily than non-affected individuals after age 60. His studies also found that people who develop Alzheimer's disease consume fewer fruits and vegetables and fewer antioxidant nutrients. These results suggest that oxidative stress and/or metabolic problems adversely affect neuronal function in Alzheimer's disease patients. This is further supported by the observations that an antioxidant blueberry extract protects neurons in culture and that gout may protect against Alzheimer's disease due to chronically elevated levels of the antioxidant uric acid.
The morning and afternoon public presentations were designed to be less technical than the scientific presentations.
Morning Session, chaired by Dr. Walter Willett (Harvard) and Dr. Balz Frei (LPI)
The first Linus Pauling Institute Prize for Health Research was presented to Dr. Bruce Ames (University of California-Berkeley) at the inaugural award banquet. Dr. Ames made a strong case for the prevention of cancer and the delay of aging with micronutrients, comparing the effect of chronic deficiency of antioxidant vitamins and B vitamins to DNA damage caused by radiation. For example, deficiencies of folate, vitamin B6, or vitamin B12 lead to chromosome abnormalities implicated in cancer. Dr. Ames estimated that poor diet is responsible for 30% of cancer cases, smoking is responsible for another 30%, chronic infections account for 20%, and the remaining 20% are probably hormonally related, while pollution and pesticides are negligible causes of cancer. The quarter of the population that consumes the lowest amount of fruits and vegetables suffers about twice the cancer rate. Dr. Ames also noted that supplementation of old rats with lipoic acid (R form, not the S form) decreases oxidative stress, restores vitamin C and glutathione levels, and removes excess iron from the brain. Old rats showed an improvement in cognitive tests after supplementation with R-lipoic acid and L-carnitine, which improves the generation of mitochondrial energy and restores cardiolipin, a lipid important in mitochondrial function. • Dr. David Ludwig (Children's Hospital, Boston) highlighted the importance of glycemic index in managing obesity. Glycemic index refers to the rate of glucose delivery to the blood after a meal. Fruits, vegetables, legumes, pasta, and nuts have a low glycemic index, whereas starchy foods like white bread, rice, and potatoes are rapidly converted into blood sugar and therefore have a high glycemic index. High-glycemic index foods also have relatively low concentrations of micronutrients and phytochemicals. A low-glycemic index diet can alter the "set point" for body weight, improve cholesterol levels, perhaps decrease the risk for diabetes, and achieve quicker satiety from meals. • Dr. Gerald Reaven (Stanford) questioned the conventional advice to replace saturated fats in the diet with carbohydrate to prevent heart disease. He argued that other risk factors, such as insulin resistance or type 2 diabetes, are accentuated by low-fat, high-carbohydrate diets. High-carbohydrate diets result in more insulin secretion, which adversely affects blood lipid parameters (elevating triglycerides and decreasing HDL cholesterol) and blood pressure in susceptible individuals. He suggested that replacing saturated dietary fats with mono- and polyunsaturated fats improves the blood lipid profile. Such a dietary modification does not necessarily result in weight gain. He concluded that the intake of saturated fat should be limited to less than 10% of total caloric intake. • Dr. Walter Willett (Harvard) reiterated the importance of replacing dietary saturated fat with unsaturated vegetable oils, particularly those with alpha-linolenic acid (e.g. canola and soybean oils), and eliminating trans fats (hydrogenated oils) in order to reduce the risk for CVD. Poland provides a good example of the rapid change from the use of saturated fats like lard and butter to non-trans fat substitutes, resulting in a lower incidence of CVD since 1990. Dr. Willett emphasized that glycemic load and the intake of trans fats are most strongly predictive of CVD. Studies have conclusively demonstrated that the high intake of fish or omega-3 fatty acid supplements reduces sudden death mortality in CVD patients. He suggested additional strategies to reduce the risk for CVD: replacing refined wheat products with whole grain products, replacing saturated fats with mono- and polyunsaturated fats (instead of carbohydrates), taking a multivitamin supplement, consuming one alcoholic drink per day, and staying lean.
Afternoon Session, chaired by Dr. Norman Krinsky (Tufts) and Dr. Paul Walter (University of Basel)
Almost 90% of lung cancers and a significant percentage of cancers of the bladder, pancreas, esophagus, and oral cavity are attributed to tobacco smoking, and about 30% of all cancer deaths in developed countries can be blamed on smoking. Dr. Stephen Hecht (University of Minnesota) informed us that there are about 4,000 chemicals in cigarette smoke, of which 55 are known to be carcinogenic. Exposure to environmental cigarette smoke also increases the risk for cancer by about 20%. Unfortunately, as yet there is no effective chemoprevention for lung cancer caused by exposure to smoke, although research progresses on the possible efficacy of vitamins and phytochemicals like isothiocyanates and myo-inositol. The damage caused by smoking may be too great to be inhibited by phytochemicals. Of course, the most effective behavior for reducing this major cancer and heart disease risk is to stop smoking. • Sonja Connor (Oregon Health & Science University) talked about the importance of docosahexaenoic acid (DHA), an omega-3 fatty acid found in fish, in brain development and eye function. DHA is concentrated in the retina, brain, and sperm and is necessary for good vision and normal brain function. Despite the importance of good DHA status, manufacturers of infant formulas in the U. S. are not required to add DHA, and mothers whose intake of fish is low also have low DHA levels in breast milk. DHA confers some protection against CVD, particularly against arrhythmia, and can be synthesized in the body from alpha-linolenic acid found in polyunsaturated fats like canola oil. • Dr. Jeffrey Blumberg (Tufts) discussed the age-related change in vitamin requirements. In particular, the elderly may commonly suffer from atrophic gastritis (decreased production of acidic gastric juice), which impairs the absorption of B vitamins. This may explain the age-related increase in plasma homocysteine, an independent risk factor for heart disease that can be decreased by folic acid, vitamin B6, and vitamin B12 supplements. Aging is also linked to a reduction in the synthesis of vitamin D in the skin, which may increase the risk of osteoporosis and impair immune function. Vitamin E supplements have been found to be of benefit against heart disease in four of six major intervention studies. Vitamin E enhances the immune response and hastens recovery time from acute infections. The long-term use of vitamin C supplements correlates with protection against cataracts, and vitamin C may also offer some protection against heart disease and cancer. Since elderly people often consume fewer calories and vitamin D-fortified dairy products, Dr. Blumberg stressed the importance of consuming nutrient-dense foods and taking vitamin supplements. • Dr. Lester Packer (University of Southern California) is the author of a recently published book, The Antioxidant Miraclealso the title of his presentation. He referred to oxygen and glucose as "dangerous friends"necessary for life and essential for energy production, but also capable of causing oxidative stress. He discussed the protection from ultra-violet radiation afforded by topically applied vitamin E and the role of vitamin E in slowing the progression of Alzheimer's disease. In his view (shared by Linus Pauling!), vitamin C is the hub of the antioxidant network in the body. He cited studies in which vitamin C was more effective than a combination of antioxidants in reducing F2-isoprostane levels (markers of lipid oxidation) in smokers and concluded that other antioxidants in the network may become relatively more important when vitamin C levels are low or marginal.
Emerging Themes (or hooray for fruits, vegetables, and vitamins)
Acknowledging the abundance of confirmed and consistent evidence from nutritional epidemiological and experimental studies, many of the experts echoed the familiar recommendation that the consumption of a diet with ample fruits and vegetables offers protection against a wide variety of cancers. Fruits and vegetables contain numerous cancer chemopreventive substances, including phytochemicals (e.g. chlorophyll, isothiocyanates, anthocyanins, carotenoids, and monoterpenes), antioxidant vitamins, B vitamins, and selenium. Additionally, tea contains a class of polyphenols that may inhibit cancer. Behavior is also an important determinant of cancer risk, which can be decreased by caloric restriction, physical activity, and refraining from smoking. Other risk factors for cancer include the consumption of red meat and saturated fat. Some phytochemicals and vitamins have become recognized as promising therapeutic agents in cancer, including monoterpenes from citrus peel and vitamins C and E.
Heart disease shares many of the same risk factors with cancer. Consumption of saturated fats and smoking significantly contribute to heart disease risk, while B vitamins that lower plasma homocysteine levels and vitamin E may lower risk. Choosing food with a low glycemic index; replacing trans fats (partially hydrogenated vegetable oil) and saturated fats with mono- and poly-unsaturated fats; consuming adequate fruits, vegetables, and nuts; substituting whole grain for refined products; and avoiding excessively high carbohydrate diets are likely to decrease significantly the risk for heart disease. Vitamin E exerts anti-inflammatory effects, potentially resulting in a decreased risk for CVD. Vitamin C and black tea have been demonstrated to enhance nitric oxide activity and normalize vascular function in patients with heart disease.
Caloric restriction, identified as protective against cancer, may also retard aging and protect against Alzheimer's disease. Additionally, antioxidant phytochemicals present in fruits, especially blueberries, and vegetables have been found to improve cognitive performance in many animals. Supplementation of animals with "age essential" micronutrients, such as L-carnitine and R-lipoic acid, reverses many of the molecular changes associated with aging and improves physical performance. Oxidative stress has been implicated in cancer, heart disease, aging, and neurodegenerative diseasesconsistent theme of the conferenceso dietary and supplementation strategies that optimize the status of the antioxidant system in the body will likely decrease the risk of age-related disease. And lastly, vitamin requirements likely increase with age, so taking a daily multivitamin supplement and getting adequate amounts of folic acid and vitamins B6, B12, C, D, and E become especially important as we become older.
Last updated November, 2001
Honoring a Scientific Giant with Nutritional Research Toward Longer, Better Lives
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