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Research Newsletter-Fall/Winter 2013

Stephen Lawson


Stephen Lawson
LPI Administrative Officer

The seventh biennial LPI Diet and Optimum Health Conference, co-sponsored by the Oxygen Club of California, convened on the OSU campus in Corvallis from May 15-18. The conference featured 28 speakers from around the world and was organized into six sessions:

  • Omega-3 Fatty Acids in Cardiovascular and Metabolic Disease Prevention
  • Vitamin D—Health Benefits Beyond Bone
  • Health Effects and Mechanisms of Action of Xanthohumol
  • Diet and Epigenetic Impacts on Disease and Aging
  • Health Benefits of Vitamin C: Beyond Scurvy
  • Micronutrients in Fertility and Pregnancy

Sixty-eight posters depicting experimental projects were displayed beginning Thursday evening. An additional eight posters were selected for oral presentations on Friday afternoon.

Additionally, Saturday morning featured a public session—Whole-food Approaches to Disease Prevention.

The Linus Pauling Institute Prize for Health Research was presented on Friday to Helmut Sies of Heinrich Heine University Düsseldorf, who gave an engrossing lecture on carotenoids, flavonoids, and oxidative stress.

Omega-3 Fatty Acids in Cardiovascular and Metabolic Disease Prevention

Chaired by Maret Traber (LPI) and Pamela Starke-Reed (NIDDK/National Institutes of Health)

  • Richard Deckelbaum (Columbia University) reviewed the health benefits of omega-3 fatty acids, commonly consumed in fish and fish oil supplements. Two important omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are inefficiently synthesized in the body from another dietary omega-3 fatty acid, alpha-linolenic acid found in flaxseed, walnuts, and vegetable oils. Omega-3 fatty acids play critical roles in cognitive and visual development, enhance immunity, delay neurodegeneration, and decrease inflammation. In mice, omega-3 fatty acids decrease cholesterol accumulation in arteries, protect against fatty liver, and, after acute administration, are neuroprotective after ischemic stroke. In humans, a high intake of omega-3 fatty acids is associated with a decreased risk for cardiac arrhythmia and sudden death from cardiovascular disease, and may help manage fatty liver disease.
  • William Harris (Health Diagnostic Laboratory, VA) discussed non-fish sources of omega-3 fatty acids, such as krill, algae, and soybean oil containing stearidonic acid (SDA), which is more easily converted to EPA than the conversion of dietary alpha-linolenic acid to EPA. Consuming six grams of SDA-fortified soybean oil raised the EPA content of red blood cells as much as consuming one gram of pure EPA.
  • William Stanley (University of Sydney, Australia) noted that supplementation with omega-3 fatty acids changes the fatty acid composition of cardiac cell membranes. This alteration decreases inflammation and is associated with protection against heart failure, although our understanding of the precise mechanisms is incomplete. Cardiac cells are rich in mitochondria, organelles that produce chemical energy in cells. DHA and EPA affect mitochondrial membrane function and improve resistance to apoptosis (programmed cell death) and, consequently, heart failure. A high intake of omega-3 fatty acids also decreases the risk for other cardiovascular events.
  • Dariush Mozaffarian (Harvard University) reported on the human studies investigating the role of omega-3 fatty acids in cardiovascular diseases. Results from such studies have been inconsistent but generally support a protective role for omega-3 fatty acids against cardiac arrhythmia and mortality. Studies indicate that there may be a threshold effect; intakes above this threshold are not associated with further improvements. He recommended to consume at least 250 mg/day of omega-3 fatty acids or at least two servings of oily fish per week.
  • Donald Jump (LPI) addressed the role of omega-3 fatty acids in nonalcoholic fatty liver disease, which is associated with obesity. The progressive form of fatty liver disease (nonalcoholic steatohepatitis or NASH) can result in cirrhosis and liver cancer. In studies of mice fed a Western-type diet (high in saturated fat, sucrose, and cholesterol), supplementation with omega-3 fatty acids, especially DHA, attenuated inflammation, oxidative stress, and fibrosis and favorably affected patterns of gene expression and metabolism, suggesting that DHA may have value in preventing fatty liver disease.
  • Vitamin D—Health Benefits Beyond Bone

    Chaired by Adrian Gombart (LPI)

  • Modern lifestyles and geographical location influence the amount of vitamin D made in the skin. Robert Heaney (Creighton University) noted that vitamin D is involved in the expression of about 10% of our genes. Randomized controlled trials (RCTs) are not well suited to address quantitative issues concerning supplementation; assessments using physiological criteria may be better. Osteomalacia (bone pain) and inadequate calcium absorption may occur when serum levels of vitamin D are below 32 nanograms/milliliter, but studies suggest that higher levels may be needed for optimal insulin responsiveness and protection against certain cancers. Based on available evidence and estimated blood concentrations in our ancestors, 40-60 ng/mL may be optimal.
  • Thomas Burne (The University of Queensland, Australia) discussed the importance of vitamin D in brain cells. Studies in Denmark found that infants with the lowest vitamin D blood levels had an increased risk for the later development of schizophrenia. In rats, vitamin D deficiency affects neurotransmitter activity, and deficiency during pregnancy adversely affects offspring. Other studies have associated low vitamin D levels with depression, brain dysfunction, and worse recovery from stroke.

  • Photo of Alan Taylor, Gary Merrill, Donald Reed

  • David Feldman (Stanford University) examined the role of vitamin D in cancer prevention, especially breast cancer. Epidemiological studies have found that vitamin D deficiency and obesity correlate with increased risk for breast cancer. In human breast cancer cells, vitamin D inhibits the expression of aromatase, an enzyme that stimulates estrogens in the breast, leading to cancer development. In obese and normal mice implanted with human breast cancer cells, vitamin D reduced tumor volume. In these experiments, vitamin D decreased aromatase and COX-2 enzymes, associated with inflammation. Vitamin D also has antiproliferative functions, inhibits angiogenesis (blood vessel formation) required by tumors, and stimulates the differentiation, or normal maturation, of cells.
  • Vitamin D deficiency is associated with an increased risk for cardiovascular diseases. Stefan Pilz (Medical University of Graz, Austria) noted that mortality from cardiovascular disease is highest in winter and in northern latitudes; both factors are associated with lower endogenous vitamin D synthesis. Obesity also causes vitamin D deficiency. The heart and vasculature have receptors for vitamin D; adequate vitamin D status lowers blood pressure and may protect against stroke and sudden cardiac death. Several large clinical trials of vitamin D supplementation and cardiovascular disease are ongoing, but the study populations were not selected for vitamin D deficiency, so results may not be definitive. Meta-analyses of other clinical trials have found that vitamin D supplementation decreases mortality, mainly caused by cardiovascular events.
  • Health Effects and Mechanisms of Action of Xanthohumol

    Chaired by Fred Stevens (LPI)

  • When hyaluronan is overproduced by cartilage cells called chondrocytes, osteoarthritis may result. Inflammatory cytokines like IL-17 stimulate the production of hyaluronan in chondrocytes, a process that may also contribute to cancer metastasis and edema. In cell-culture experiments, Peter Prehm (Münster University Hospital, Germany) showed that the flavonoid xanthohumol, commonly extracted from hops used to make beer and from horny goat weed, inhibited hyaluronan export from cells and prevented collagen degradation. Curcumin from the spice turmeric also inhibited hyaluronan export from cells.

  • Photo of David Ludwig, Edgar Miller III, Eric Rimm, Fionna Harrison
  • Since the metabolite of an isomer of xanthohumol called isoxanthohumol is a phytoestrogen, Richard van Breemen (University of Illinois) has been studying its possible use in hormone-replacement therapy for menopausal symptoms. Xanthohumol and related compounds inhibited drugmetabolizing enzymes in vitro, suggesting the need for in vivo human studies. Xanthohumol is slowly absorbed into the blood stream and excreted in bile, with a half-life in the body of about 20 hours.
  • Fred Stevens (LPI) noted that 2013 marks the 100th anniversary of xanthohumol research. Xanthohumol has anticancer, anti-inflammatory, and anti-hyperglycemic effects. In a rat model of metabolic syndrome, xanthohumol decreased body weight, fasting plasma glucose and fatty acid levels, and products of dysfunctional lipid metabolism. Xanthohumol also decreased reactive oxygen species by stimulating the synthesis of glutathione, an endogenous antioxidant.
  • Diet and Epigenetic Impacts on Disease and Aging

    Chaired by Rod Dashwood (LPI) and Joe Beckman (LPI)

  • Kent Thornburg (Oregon Health & Science University) discussed the influence of fetal and maternal nutrition (“programming”) and birth weight on the risk for chronic diseases later in life. Infants born to mothers who have either low- or high-caloric malnutrition have a higher risk for coronary heart disease and metabolic syndrome. Very low birth weights predict a higher risk for diabetes, hypertension, metabolic and neurological deficits, and cardiac mortality. Additionally, fetal nutrition affects subsequent generations—oocytes are formed in fetuses that later mature into eggs. Poor fetal nutrition can lead to structural abnormalities in organs, such as smaller hearts, or fewer neurons. For example, the number of cardiac muscle cells in adult sheep is predetermined during gestation, when proper nutrition is crucial.

  • Photo of Adrian Gombart, Maret Traber and Barbara McVicar
  • Sang-Woon Choi (Tufts University) discussed the epigenetic impact of the chemical modification of DNA by methylation (addition of a CH3 group) and hydroxymethylation (addition of a CH2-OH group)—influenced by diet and age—that affects gene expression. Methylation involves several B vitamins and can be influenced by dietary factors like sulforaphane in broccoli or polyphenols in tea. Feeding alcohol to young and old mice reduced hydroxymethylation only in young mice, which may inhibit gene expression. Such epigenetic influences can determine the phenotype—how genes are expressed—resulting in alterations in vulnerability to disease.
  • A dramatic example of epigenetic influence is the “Dutch Hunger Winter” of 1944-5 during which the Dutch faced famine, including micronutrient deficiencies, because of WWII. Sixty years later, the offspring of mothers who endured the famine had increased risk for obesity, cancer, and cardiovascular diseases. Susan Duthie (University of Aberdeen, UK) noted that folate deficiency is among the most common micronutrient deficiencies in the world and affects oxidative stress and gene expression through altered DNA methylation (an epigenetic event), synthesis, and repair. In mice fed a high-fat diet, folate deficiency a ccelerated atherosclerotic plaque development.
  • Donato Romagnolo (University of Arizona) discussed the epigenetic modification of BRCA-1, a gene whose product—a tumor-suppressor protein—is decreased in sporadic breast cancer. A diet rich in fruits and vegetables decreases the risk of mutations in BRCA-1. The activity of the gene that triggers the synthesis of BRCA-1 may be increased by dietary factors, leading to the activation of tumor suppressor genes and the silencing of oncogenes.
  • Clarissa Gerhäuser (German Cancer Research Center, Heidelberg) studies the methylation of genes associated with breast and prostate cancer. Polyphenols in food and tea, selenium, curcumin, isothiocyanates and sulforaphane from cruciferous vegetables, and lycopene all affect DNA methylation in vitro and may reduce cancer risk. In cancer cells, hypermethylation of DNA may lead to increased metastasis. Gene methylation is often associated with changes in cell proliferation, growth, and death. Methylation inhibitors have been found to dose-dependently inhibit breast cancer in vitro.
  • MicroRNAs are small non-coding RNA molecules that regulate gene expression. Alberto Izzotti (University of Genoa, Italy) noted that microRNA activity can be modulated by vitamins A, B, D, and E; selenium; curcumin; resveratrol; catechins (polyphenols in tea, chocolate, grapes, berries); and indole-3-carbinol and isothiocyanates from cruciferous vegetables and discussed their importance in cancer chemoprevention. Some of these substances protect the enzyme DICER—involved in microRNA maturation—from being blocked by carcinogens like those in cigarette smoke or by mutagens in meat cooked at high temperatures.
  • Health Benefits of Vitamin C: Beyond Scurvy

    Chaired by Balz Frei (LPI)

  • Over 40 years ago, Linus Pauling and Ewan Cameron reported favorable responses in terminal cancer patients receiving vitamin C. Garry Buettner (University of Iowa) reviewed our current understanding of the anticancer mechanisms of vitamin C. Despite the powerful antioxidant properties of vitamin C, in very high concentrations it can produce hydrogen peroxide in the body that can kill susceptible cancer cells. High oral doses of vitamin C can raise plasma levels to about 80 micromolar, but intravenous infusions of 100 grams raise plasma concentrations to more than 250 times greater (20 millimolar). In a small clinical trial in patients with pancreatic cancer, large infusions (up to 100 grams) of vitamin C combined with gemcitabine have resulted in increased survival times. It’s uncertain if vitamin C is selectively cytotoxic to cancer cells or mainly cytostatic. Vitamin C infusions also decrease levels of F2-isoprostanes, biomarkers of oxidative stress.
  • Edgar Miller, III (Johns Hopkins University) conducted a meta-analysis of 29 clinical trials (with a total of over 1,400 subjects) on vitamin C and blood pressure reported between 1966 and 2011. The median dose of vitamin C was 500 mg/day for a median duration of eight weeks. Vitamin C supplements reduced systolic blood pressure (SBP) by 3.8 mm Hg and diastolic blood pressure (DBP) by 1.5 mm Hg. In hypertensive subjects, vitamin C reduced SBP by 4.9 mm Hg and DBP by 1.7 mm Hg. In other short-term studies, vitamin C has lowered uric acid levels and improved flow-mediated vasodilation, or arterial relaxation. Long-term trials are needed to determine the duration of benefit.

  • Photo of Clarissa Gerhäuser and Jessica Keune
  • Fiona Harrison (Vanderbilt University) addressed the role of vitamin C in brain aging and cognitive function. Vitamin C is an antioxidant and participates in neurotransmitter synthesis. In mouse models of aging and Alzheimer’s disease, parenteral administration of vitamin C by injection or intravenous infusion improves learning and memory. In the Alzheimer’s disease model, a 25% decrease in vitamin C levels in the brain is associated with oxidative damage and beta-amyloid pathology. In a test of physical stamina, mice with low vitamin C levels performed worse than those with higher levels. Based on NHANES 2009-10 data, as much as 30% of the American population may be vitamin C inadequate.
  • Micronutrients in Fertility and Pregnancy

    Chaired by David Williams (LPI)

  • Helene McNulty (University of Ulster, Northern Ireland) discussed the critical role of maternal folate intake in preventing neural tube defects and, possibly, facial clefts and heart defects in infants. The neural tube in embryos closes at about the time when a woman may suspect that she is pregnant, so consistent supplementation through fortified foods or a multivitamin/mineral supplement during periconception is important. In clinical trials, supplemental folic acid reduced stroke incidence by about 20% in people without a history of stroke. The B vitamin riboflavin may lower blood pressure, depending on genotype. Folate status is inversely correlated with homocysteine levels, which are associated with an increased risk for cardiovascular diseases. Fortified food contains folic acid, which is more bioavailable than the folate found naturally in food. Food folate can be destroyed by cooking, and food sources are limited. Folic acid converts to folate in the body in about 90 minutes.
  • Kelton Tremellen (University of South Australia) talked about the role that micronutrients play in fertility and early fetal development. Oxidative stress adversely affects the quality and motility of sperm, as well as DNA integrity. Antioxidants like vitamins C and E, zinc, selenium, carotenoids, and lycopene can attenuate oxidative damage and improve fertility. Oxidative stress is also implicated in erectile dysfunction and female reproductive abnormalities. Additionally, low levels of vitamin D in pregnancy are associated with an increased risk for asthma and schizophrenia in offspring. Low maternal levels of folate, which can affect methylation, are linked to a higher risk for miscarriage. Low-iodine levels are associated with decreased sperm quality. While excess iron may cause adverse effects, appropriate iron levels help in ovulation.
  • Victoria Moran (University of Central Lancashire, UK) addressed the importance of micronutrients like iron, iodine, and zinc on brain development in the fetus. Over 50% of premenopausal women have insufficient iron status, and iron-deficient anemia is prevalent around the world. Iron is important in energy metabolism, neurotransmitter function, and myelin synthesis. While animal studies indicate that maternal iron deficiency results in irreversible deficits in offspring, human studies show that iron treatment in iron-deficient children improves cognitive development and function. Although there is no good biomarker for zinc status in humans, zinc deficiency in animals results in poor attention and learning. There are “windows of sensitivity” during which micronutrient status importantly affects fetal development. The magnitude of the effect of micronutrient status in infants and children may be influenced by context—poverty, nutrient interactions, multiple deficiencies, parent-infant relationships, physical closeness between parents and infants, and breast-feeding, which can be a good source of the omega-3 fatty acid docosahexaenoic acid important in brain development.

  • Photo of Carmen Wong, Lauren Atwell, Emily Ho, Laura Beaver, Gregory Watson

    Oral Abstracts

    Chaired by Viviana Perez (LPI) and Kathy Magnusson (LPI)

    Eight posters were selected for oral presentation:

  • For the Oregon Brain Aging Study, Gene Bowman (Oregon Health & Science University) measured omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid) in the plasma of older adults without dementia or Alzheimer’s disease. Those subjects with the highest levels of omega-3 fatty acids had a delay of one year in the decline of age-related, executive cognitive function, possibly due to a reduction in the number of brain lesions.
  • Previous research has found that a multivitamin/mineral supplement (MVM) containing guarana, a fruit from trees native to the Amazon, improved executive cognitive and memory functions. The present study by Andrew Scholey (Swinburne University, Australia) addressed whether guarana or the MVM was responsible for those effects in 20 healthy, young adults. Subjects who got the MVM with guarana showed improved attention, memory performance, and mood compared to those who got a placebo. Compared to placebo, the MVM with and without guarana increased brain activity in the area associated with memory, which was more pronounced in those taking the MVM with guarana.
  • In a study reported by Özgür Sancak (Bayer Consumer Care, Switzerland), the effect of vitamin C on gene expression and inflammation was examined in five healthy subjects who got one gram daily of vitamin C for five days. Blood taken from the subjects and exposed to an inflammatory stimulus exhibited a pattern of gene expression different from that in unstimulated blood; specifically, vitamin C increased the amount of interleukin 10, an anti-inflammatory cytokine, and decreased NF-κB, a marker of inflammation.
  • Cancer cells in a solid tumor become hypoxic (oxygen deprived) because of inadequate angiogenesis (blood vessel formation), which affects their response to chemotherapy and radiation. Hypoxia-inducible factor-1 (HIF-1), which is elevated in hypoxic tumor cells, mediates angiogenesis and glucose transport and can be turned off by reactions that require vitamin C. After analyzing samples of normal and colorectal cancer tissue from 50 patients, Margreet Vissers (University of Otago, New Zealand) reported that vitamin C levels were lower in tumor tissue and correlated inversely with HIF-1 activity, tumor size, and necrosis. High levels of vitamin C in tumor cells were also associated with longer patient survival.
  • Laura Beaver (LPI) discussed the effect of sulforaphane from cruciferous vegetables on gene expression in normal and cancerous prostate cells. Sulforaphane altered expression of about 3,000 genes, especially those involved in cell cycle, proliferation, apoptosis, and angiogenesis in cancer cells, thereby killing cancer cells but not normal cells. Its effects vary depending on the specific stage of carcinogenesis.
  • Polyphenols in fruits and vegetables and their metabolites are associated with some protection against colon cancer. Joanna Kaniewska (University of Aberdeen, UK) examined the effect of polyphenols in a diet enriched with 7.5 servings of fruits and vegetables per day on gene regulation in normal human colon cells, urine, plasma, and feces collected from 21 human subjects who consumed the enriched diet for 12 weeks. Various polyphenols were associated with increased antioxidant protection and DNA stability.
  • High consumption of soy is associated with a lower incidence of breast cancer in Asian women. Ben O. de Lumen (University of California-Berkeley) discussed the role of lunasin, a peptide found in soy, peanuts, and seeds and in the Soy Bowman Birk Inhibitor (BBI) Concentrate currently being tested in clinical trials, on human breast cancer cells implanted into mice. Intraperitoneally injected lunasin, but not BBI, effectively inhibited tumor growth and killed cancer cells. However, BBI protects lunasin from digestion when eaten, thereby improving its bioavailability.
  • Levels of klotho, a protein found in cell membranes, decline with age. Klotho-deficient mice exhibit short lifespan, kidney disease, osteoporosis, skin atrophy, and dysregulation of vitamin D. John Finnell (AOMA Graduate School of Integrative Medicine, Texas) gave 10,000 IU/day of vitamin D3 for 12 weeks to 40 adults with vitamin D insufficiency (<30 ng/mL) and then measured plasma klotho concentrations. Plasma levels of vitamin D increased after supplementation, and levels of klotho significantly increased as well.
  • Young Investigator Awards

    Four young scientists were selected for Young Investigator Awards:

  • Molly Derry (University of Colorado), for her presentation “Investigating grape seed extracts chemopreventive efficacy in in-vitro and in-vivo models of colorectal cancer”
  • Erica Sharpe (Clarkson University), for “Effect of brewing conditions and re-infusion on the antioxidant capacity of green tea: A side-by-side analysis using the ORAC and NanoCerac assays”
  • Rachel Botchlett (Texas A&M University), for “Effects of a high-fat diet and metformin treatment on sarcolemmal and insulin signaling protein expression in young mice”
  • Yasmeen Nkrumah-Elie (LPI), for “Biomarkers of zinc deficiency”

  • Photo of Molly Derry, Rachel Botchlett, and Erica Sharpe

    Public Session: Whole-food Approaches to Disease Prevention

    Chaired by Emily Ho (LPI) and Balz Frei (LPI)

  • Penny Kris-Etherton (The Pennsylvania State University) reviewed the influence of whole grains and nuts on cardiovascular and metabolic diseases. Ischemic heart disease and stroke have been identified as, respectively, the number one and number three health problems in the world. Significant risk factors include high blood pressure and low consumption of whole grains, seeds, and nuts. Many studies have shown that high consumption of whole grains, including wheat, oats, rye, rice, and popcorn, is associated with lower body mass index (BMI), blood pressure, and cholesterol levels, and a decreased risk for metabolic syndrome. One study with 50 adults given six servings of refined or whole grains per day for 18 weeks found that whole grains reduced the prevalence of prediabetes by 90%. Nut consumption reduces the risk for cardiovascular disease and associated morbidity and mortality in a dose-response manner. Nuts also reduce cholesterol and triglycerides, lower blood pressure, reduce oxidative stress and inflammation, and improve vascular function.
  • Eric Rimm (Harvard University) discussed the health effects of polyphenols present in fruits, vegetables, and some beverages. Different polyphenols have subtle differences in chemical structure that affect their biological activity and health benefits. Phenolic acids are found in olives, coffee, wine, nuts, and spices. Berries, wine, and nuts contain stilbenes. Lignans are present in sesame and olive oils, flaxseed, and whole grains. Flavonoids are found in berries, apples, chocolate, wine, and tea. Generally, polyphenols improve vascular function, lower blood pressure and lipids, and help with glycemic control. Processing, including cooking, and exposure to sunlight affect the concentration of polyphenols in food. Blueberries and strawberries contain a flavonoid called anthocyanin, and in a large study, blueberries (2-4 servings per week) were found to be especially effective in lowering the risk for hypertension, diabetes, stroke, and heart disease.
  • Cynthia Thomson (University of Arizona) emphasized that dietary habits can affect the risk for breast cancer and metabolic syndrome that is associated with diabetes risk. Breast cancer is the most common type of cancer in women, and among 35- to 55-year-old American women, it is the leading cause of death. Several themes to reduce breast cancer risk emerged from her presentation: limit alcohol and eat nutrient-dense food, less fat, more vegetables high in carotenoids, spices, and high-fiber food. Metabolic syndrome is characterized by high blood sugar, elevated lipids, large waist circumference, and high blood pressure. If not corrected, it can progress to diabetes. Avoiding simple sugars and consuming high-fiber foods are protective. Maintaining a good BMI helps to prevent breast cancer and metabolic syndrome.
  • The incidence of childhood obesity is rising in the US, which may shorten life expectancy by two to five years. It affects not only all the body’s organs but also psychosocial development. David Ludwig (Harvard University) discussed the importance of an integrated, family-based approach to solving this problem. Children may express preference for sweet, salty, and fatty foods, but this is largely programmed by adults. Establishing a parenting style that favors health is the key to successful weight management in children. A diet low in simple carbohydrates is better than a low-fat diet for losing weight, since calories from fat have declined while obesity rates have increased. Exercise in children may not overcome the effect of overwhelming caloric intake, but, if regular and fun, it may help.

  • Last updated October 2013