Progress 11/01/99 to 10/31/04
Outputs
1. What major problem or issue is being resolved and how are you resolving it (summarize project aims and objectives)? How serious is the problem? What does it matter? The Dietary Antioxidants, Aging and Oxidative Stress Status CRIS is comprised of the Antioxidants Research Laboratory (ARL) and the Carotenoids and Health Laboratory (CHL). The generation of oxygen free radicals during cellular metabolism and by certain environmental factors, including lifestyle, appears to play a critical role in the aging process. High dietary intakes of antioxidant vitamins and phytochemicals are associated with better maintenance of physiologic function and a lower prevalence of many degenerative conditions in older adults. Understanding how antioxidants, especially the phytochemical carotenoids and flavonoids, reduce oxidative stress and impact the pathogenesis of chronic disease present opportunities for health promotion and alternative therapeutic modalities for an aging
population. The ARL conducts studies to understand the role of dietary antioxidants, particularly the flavonoids in conjunction with vitamins C and E, on free radical reactions and changes in oxidative stress status during aging. Lipid, protein, nucleic acid and other cellular targets of oxidative damage are assessed in experimental models and in healthy and other human populations to elucidate antioxidant requirements for optimal health. These projects contribute to the description and prediction of the impact of antioxidants and oxyradicals on age-related changes in nutrient requirements and chronic degenerative conditions. The CHL investigates dietary carotenoids and healthy aging through the following study areas: (i) The bioavailability of carotenoids (ss-carotene, lycopene, and lutein) and vitamin A equivalence of provitamin A carotenoids using intrinsically labeled spinach, collard greens, tomatoes, and carrots; (ii) The development and application of a biomarker assay of total
antioxidant capacity in both the lipid and aqueous compartments of biological samples; and (iii) A functional role of carotenoids in eye health, particularly in age-related macular degeneration. There is a compelling body of scientific evidence that suggests that free radical pathology is associated with many of the chronic diseases that are common among older adults, e.g., cancer, heart disease, and degenerative eye disorders such as cataracts and macular degeneration. Though not so extensively explored, several recent studies suggest antioxidants may also play a preventive or adjunctive role in conditions like arthritis, diabetes, and Parkinson's disease. However, definitive evidence is absent in all of these cases. Quantitative information linking dietary requirements for antioxidants, validated biomarkers of intermediary oxidative stress events and status, and health and aging outcomes is lacking. Such information is necessary to the development of scientifically based
recommended dietary allowances, including tolerable upper limits of intake for antioxidant nutrients across the lifespan and particularly for the elderly. Further, the conversion efficiency of ss- carotene to vitamin A in humans needs to be comprehensively quantified. Research within these laboratories falls under National Program 107 - Human Nutrition, Components 1: Nutrient requirements and 7: Bioavailability of nutrients and food components. 2. List the milestones (indicators of progress) from your Project Plan. To characterize age-related changes in antioxidants and oxidative stress status in healthy elderly as well as in clinical and experimental models of accelerated aging and the effect of dietary interventions on these parameters to better define dietary antioxidant requirements during aging. To elucidate the bioavailability and bioconversion of dietary carotenoids and their impact on the prevention of macular degeneration, night blindness, and cancers of the breast and
prostate. 3. Milestones: A. Study results were completed for serum response to food provitamin A carotenoids and their conversion to vitamin A in healthy adults who were fed spinach and carrots. Quercetin metabolism study was completed. Quercetin is a flavonoid abundant in onions, tomatoes, tea and red wine in rats. Further Quercetin studies are proposed in the new project plan currently in the OSQR process. A human study of dietary antioxidant intake and plasma antioxidant status over time in patients, 50-89 years of age, following acute ischemic stroke (AIS) was completed. B. Replacement Project is pending OSQR certification. 4. What were the most significant accomplishments this past year? A. Single most significant accomplishment during FY2004: Serum response to food provitamin A carotenoids and their conversion to vitamin A were investigated by the CHL in healthy adults who were fed spinach and carrots that were hydroponically grown using stable isotopes in the nutrient
solution. Our results showed that in the areas under the total serum responses curves of spinach, ss-carotene was less bioavailable than carrot ss-carotene. Spinach ss-carotene conversion to retinol was 22 to 1 and carrot ss-carotene to retinol was 15 to 1, on a weight basis. Our results confirm that green and yellow vegetables provide a substantial amount of vitamin A and the food matrix greatly affects bioavailability of plant carotenoids and its conversion to vitamin A. The use of plant provitamin A as a sustainable and effective strategy in combating vitamin A deficiency in various parts of the world, from an array of plant sources, needs continued scientific and quantitative evaluation. B. Other significant accomplishments: 1. The ARL studied quercetin, a flavonoid abundant in onions, tomatoes, tea and red wine. Research studies suggest that quercetin may reduce the risk of some age-related chronic diseases, but an incomplete understanding of its bioavailability and metabolism
confounds the interpretation of these results. To investigate the hypothesis that dietary quercetin is metabolized in the gastrointestinal (GI) tract before or during absorption, portions of this tissue and its lumen contents were analyzed from rats fed quercetin. We identified 14 quercetin metabolites as various types and isoforms of methyl, sulfate and glucuronide conjugates. Less then 10% of quercetin in luminal contents and >65% in GI tissues were metabolized. Stomach tissue contained 4 different metabolites of quercetin while stomach contents showed no evidence of biotransformation. Metabolism was greatest in the small intestine where 95% of the quercetin was metabolized, principally into mono-glucuronide conjugates. In the lumen of the small intestine only 9% of the quercetin was metabolized, forming equal amounts of 3 different classes of metabolites. Cecum and colon contained 9 different quercetin conjugates, while their luminal contents held only trace amounts of
quercetin metabolites. These results demonstrate that GI tissue, especially small intestine, is a major site of quercetin metabolism in rats, and suggest that the metabolism of dietary quercetin may be predominantly a pre-systemic event. 2. Animal studies suggest that ischemia-reperfusion associated with acute ischemic stroke (AIS) may promote oxidative stress and contribute to brain injury. The ARL examined dietary antioxidant intake and plasma antioxidant status during very early (<8 hours), early (24-48 hours and 3- 5 days) and recovery (4-6 weeks) phases following AIS in 30 patients aged 50-89 years. Mean plasma total antioxidant capacity measured by Oxygen Radical Absorbance Capacity (ORAC) in the early and 24-48 hour post- stroke phases was 14% and 18% lower than recovery phase and 8% and 12% lower than 27 healthy controls aged 74-85 years. Plasma ascorbate and alpha-tocopherol fell by 16-21% and 9-15% during the early post-stroke phases and returned toward baseline during
the recovery period. Vitamin C intake correlated with plasma ascorbate but intakes of vitamins C and E were not directly associated with plasma ORAC or alpha-tocopherol. These results indicate an early depletion of antioxidant defenses following AIS. Although the possibility that reduced intake may contribute to diminished antioxidant status 1-5 day post-stroke cannot be excluded, reduced plasma antioxidant capacity within hours of onset is consistent with increased antioxidant consumption during early ischemic brain injury in humans. C. Significant activities that support special target populations: None. 5. Describe the major accomplishments over the life of the project, including their predicted or actual impact. These accomplishments are linked to National Program 107 Human Nutrition. During the life of this project, some of the major accomplishments of the CHL have been: 1. Provitamin A carotenoids (mainly beta-carotene) can provide vitamin A nutrition for humans, but the
efficiency of production of vitamin A from dietary provitamin A carotenoids is quite a bit less than previously thought. The laboratory investigated in vivo bioconversion of beta- carotene to vitamin A after a physiological dose of beta-carotene in oil capsule, spinach beta-carotene, or carrot beta-carotene. Our results showed that the conversion factor of beta-carotene (6.0 mg in oil) to retinol in well-nourished adults varied from 2.4 to 20.2 (n=22), and the average conversion factor was 9.1 to 1 on a weight basis or 4.8 to 1 on a molar basis. The conversion factor of spinach carotenes to vitamin A was 22 to 1 and that of carrot carotenes to vitamin A was 15 to 1 (n=7). These conversion factors are greater than the presently accepted 12 to 1 ratio for dietary beta-carotene to vitamin A, the factor currently used for calculating the vitamin A value of plant carotenes in the United States. Action Plan components 1: Nutrient Requiremnets and 7: Bioavailability of Nutrients and Food
Components. 2. Currently available biomarkers of plasma antioxidant capacity use hydrophilic radical generators, which only produce radicals in the aqueous compartment of plasma that is made up of both aqueous and lipid compartments. We can now determine the "true" antioxidant capacities in both the aqueous and lipid compartments of human plasma. Our studies indicated that the antioxidant nutrients present in both the aqueous and lipid compartments (carotenoids and tocopherols) are capable of removing free radicals generated in plasma, and their activity depends on the localization of the attacking radical species. Our studies also suggested that the beneficial effect of high intakes of fruits and vegetables on the risk of degenerative/chronic diseases may not rely on the effect of a single antioxidant but rather on a concerted action of several antioxidant nutrients. Action Plan component 7: Bioavailability of Nutrients and Food components. 3. Meso-zeaxanthin, in addition to
lutein and all-trans zeaxanthin, is another major carotenoid that makes up the macular pigment. Meso- zeaxanthin is not found in diet but probably results from chemical processes occurring with in the eye. In collaboration with Dr. Snoderly of the Schepens Eye Research Institute, we used monkeys as a model to study macula pigment. Our experiments in monkeys have shown that lutein is the precursor of meso-zeaxanthin. This conversion may help explain, in part, the individual variation in macular pigment response to lutein supplementation. Action Plan components 1: Nutrient Requiremnets. 4. Bioavailability of dietary lutein has not been well studied. We have compared the bioavailability of lutein in eggs, spinach, and supplements in healthy adult men using carotenoid response in serum and chylomicrons. Our results found lutein to be ~3 times more bioavailable in eggs than in spinach or supplements and no differences in responses between spinach and supplements. These results provide
evidence that eggs are a highly bioavailable source of lutein when compared to more conventional sources. Action Plan components 1: Nutrient Requiremnets and 7: Bioavailability of Nutrients and Food Components. During the life of this project, some of the major accomplishments of the ARL have been: 1. Consumption of nuts has been associated with a reduced risk of coronary heart disease. As the antioxidant polyphenolic compounds in nuts, found especially in their skins, may contribute to this putative benefit, we examined their bioavailability and activity in hamsters. Isorhamnetin, kaempferol, quercetin, epicatechin, and catechin reached peak plasma concentrations at 1 hour and returned to baseline by 10 hours. LDL collected at 1 hour did not differ from baseline samples in resistance oxidation but the in vitro addition of vitamin E significantly increased lag time relative to controls. Thus, we found almond skin polyphenolics are bioavailable and work in synergy with vitamin E to
protect LDL against oxidation. Action Plan components 6: Health Promoting Properties of Plant and Animal Foods and 7: Bioavailability of Nutrients and Food Components. 2. Observational studies suggest increased consumption of dietary flavonoids may be inversely related to risk of coronary heart disease. Dark chocolate can be a rich source of cocoa flavanols and procyanidins that have antioxidant properties and enhance endothelial nitric oxide and prostacyclin production. We conducted a clinical trial in healthy subjects randomized to receive either low or high flavonoid dark chocolate bars daily. Vascular responsiveness (endothelium-dependent flow-mediated dilation) was greater in the high vs. low flavonoid group. Despite a marked increase in plasma epicatechin concentrations, no significant differences were noted in the resistance to LDL oxidation, ORAC values, plasma lipids or lipoproteins, blood pressure, or body weight. Thus, flavonoid-rich dark chocolate can improve endothelial
function in healthy adults independent of a marked effect on biomarkers of oxidative stress. Action Plan components 6: Health Promoting Properties of Plant and Animal Foods and 7: Bioavailability of Nutrients and Food Components. 3. Polyphenols may act as antioxidants directly by quenching reactive oxygen species and indirectly by chelating transition metals. However, their interaction with the antioxidant vitamins C and E have not been carefully examined. We found that even at very low levels, when flavonoids are combined with vitamins E and C, they act in synergy, i.e., in a fashion where the sum of their actions is much greater than each nutrient alone, to protect against LDL oxidation and appear to play a co- defensive role against atherogenesis. Action Plan components 1: Nutrient Requiremnets and 7: Bioavailability of Nutrients and Food Components. 4. Muscle damage resulting from eccentric exercise provides a useful model of free radical-induced injury and age-related
responses to oxidative stress. We completed a randomized clinical trial of vitamin E supplementation in healthy young and older men undergoing an intense bout of downhill running. Vitamin E was found to prevent exercise-induced increases in selected measures of lipid and nucleic acid oxidation but these changes were dependent, in part, upon age. In contrast, we completed a clinical trial of vitamin E supplementation in older adults with rheumatoid arthritis but were unable to demonstrate any benefit to the intervention. Action Plan components 1: Nutrient Requiremnets and 6: Health Promoting Properties of Plant and Animal Foods. 6. What science and/or technologies have been transferred and to whom? When is the science and/or technology likely to become available to the end- user (industry, farmer, other scientists)? What are the constraints, if known, to the adoption and durability of the technology products? The research accomplishments of the CHL have been presented at several
forums to research scientists, policy makers, and health journalists including: (a) Lutein Supplement Studies in Humans: Recent Studies, Carotenoids Research Initiative Group, Washington DC; (b) Resistance to Oxidative Stress Following Carotenoid Supplementation in Humans, Oxygen Club of California, Santa Barbara, CA; (c) Synergistic Antioxidant Actions of Carotenoids, Gordon Conference on Carotenoids, Ventura, CA. The research accomplishments of the ARL have been presented at several forums to research scientists, healthcare providers, and policy makers including: American Society for Horticultural Science, Providence, RI; University of Chicago, Chicago, IL; SupplySide East International Trade Show and Conference, Secaucus, NJ; First International Scientific Symposium on Eggs and Human Health, Washington, DC; California Avocado Commission, Rancho Valencia, CA; University of Arizona, Tucson, AZ; Administracion Nacional de Medicamentos Alimentos y Tecnologia, Buenos Aires, Argentina;
Eastern Tennessee State University, Johnson City, TN; University of Massachusetts Medical School, Worcester, MA; New York Academy of Sciences Conference on Vitamin E and Health, Boston, MA. 7. List your most important publications in the popular press and presentations to organizations and articles written about your work. CHL research was highlighted on the website http://www. foodproductiondaily.com/news/news-NG.asp?id=51668 regarding beta-carotene levels being to low for adequate vitamin A nutriture. ARL research was presented in stories several media outlets including: Print media - Boston Magazine; United Press International; PR Newswire; Los Angeles Times; AARP - The Magazine; Newsday; Washington Post; Wall Street Journal; Newsday; Review of Ophthalmology; Alternative Medicine; USA Today; Providence Journal; Cooking Light; Reader's Digest; Alternative Medicine; Newsweek; Sacramento Bee; Bottom Line Personal; Natural Health; Woman's Day; Health Day; St. Petersburg Times;
Prevention; Shape. Websites - Forbes.com. Radio - WLPO, Chicago, IL; WAJK, Chicago, IL; JKOT, Chicago, IL; WOR, New York, NY. TV - WHDH-TV (NBC), Boston, MA; NECN-TV, Boston, MA.
Impacts
(N/A)
Publications
- Ameho, C.K., Martin, A., Milbury, P.E., Blumberg, J. 2004. Effect on quercetin intake on biomarkers of oxidative stress in f344 rats fed vitamin e replete or deficient diets. Journal of Federation of American Societies for Experimental Biology. 18(5 Part II):A908.
- CHEN, C., MILBURY, P., KWAK, H., LI, T., BLUMBERG, J. EFFECT OF ALMOND POLYPHENOLICS ON ANTIOXIDANT CAPACITY IN OLDER ADULTS. JOURNAL OF FEDERATION OF AMERICAN SOCIETIES FOR EXPERIMENTAL BIOLOGY. 2004;18(5 PT II) :A906.
- RIBAYA-MERCADO, J.D., HUGHES, C.D., JOHNSON, E., BLUMBERG, J.B., MAYNE, S. T., CARTMEL, B. SERUM XANTHOPHYLL BUT NOT HYDROCARBON CAROTENOIDS ARE INVERSELY ASSOCIATED WITH URINARY F2-ISOPROSTANES IN CURATIVELY-TREATED EARLY STAGE HEAD AND NECK CANCER PATIENTS. EXPERIMENTAL BIOLOGY. 2004;18(4 PT I):A534.
- TANG, G., QIN, J., DOLNIKOWSKI, G.G., RUSSELL, R.M. SHORT-TERM (INTESTINAL) AND LONG-TERM (WHOLE BODY) CONVERSION OF BETA-CAROTENE TO VITAMIN A IN ADULTS USING A STABLE ISOTOP REFERENCE METHOD. AMERICAN JOURNAL OF CLINICAL NUTRITION. 2003;78:259-66.
- FERREIRA, A.L., YEUM, K.J., RUSSELL, R.M., KRINSKY, N.I., TANG, G. ENZYMATIC AND OXIDATIVE METABOLITES OF LYCOPENE. Journal of Nutritional Biochemistry. 2003;14:531-540.
- JOHNSON, E.J. A BIOLOGICAL ROLE FOR LUTEIN (REVIEW). Food Reviews International. 2004;20:1-16.
- KRINSKY, N.I., YEUM, K. CAROTENOID-RADICAL INTERACTIONS. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS. 305:754-60,2003.
- YEUM, K., RUSSELL, R.M., KRINSKY, N.I., GIANCARLO, A. SYNERGISTIC INTERACTIONS OF BETA-CAROTENE, ALPHA-TOCOPHEROL AND ASCORBIC ACID IN DELIPIDIZED HUMAN SERUM ENRICHED WITH PHOSPHATIDYL. JOURNAL OF FEDERATION OF AMERICAN SOCIETIES FOR EXPERIMENTAL BIOLOGY. 2004;18(4 Part I):A480.
- TANG, G., QUIN, J., DOLNIKOWSKI, G.G., RUSSELL, R.M., GRUSAK, M.A. VITAMIN A VALUE OF SPINACH AND CARROTS AS ASSESSED USING A STABLE ISOTOPE REFERENCE METHOD IN ADULTS. JOURNAL OF FEDERATION OF AMERICAN SOCIETIES FOR EXPERIMENTAL BIOLOGY. 2004;18(4 Pt I):A157.
- SHIM, Y.J., YEUM, K., TANG, G., AHN, S.H., RUSSELL, R.M., LEE-KIM, Y.C. RETINOIC ACID ISOMERS AND CAROTENOID LEVELS IN SERUM AND BREAST ADIPOSE TISSUE OF BENIGN BREAST TUMOR OR BREAST CANCER. JOURNAL OF FEDERATION OF AMERICAN SOCIETIES FOR EXPERIMENTAL BIOLOGY. 2004;18(4 Part I):A498.
- JOHNSON, E.J. NUTRITION AND THE AGING EYE. IN: BALES C., RITCHIE C., ED(S). HANDBOOK OF CLINICAL NUTRITION AND AGING. TOTOWA, NJ: HUMANA PRESS INC. 2004:193-209.
- Blumberg, J.B. 2003. Introduction to the proceedings of the third international scientific symposium on tea and human health: role of flavonoids in the diet. Journal of Nutrition. 133:3244S-6S.
- Chen, C., Milbury, P., Kwak, H., Collins, W.F., Samuel, P., Blumberg, J.B. 2004. Avenanthramides and phenolic acids from oats are bioavailable and act synergistically with vitamin c to enhance hamster and human ldl resistance to oxidation. Journal of Nutrition. 134(6):1459-66.
- Engler, M.B., Engler, M.M., Chen, C.Y., Malloy, M.J., Bowne, A., Chiu, E.Y. , Kwak, H., Milbury, P., Blumberg, J., Mietus-Snyder, M.L. 2004. Flavanoid- rich dark chocolate improves endothelial function by increasing plasma epicatechin concentration in health adults. Journal of American College of Nutrition. 23(3):197-204.
- LIU, C., RUSSELL, R.M., SMITH, D.E., BRONSON, R.T., MILBURY, P.E., FURUKAWA, S., WANG, X., BLUMBERG, J.B. THE EFFECT OF DIETARY GLUTATHIONE AND COENZYME Q10 ON THE PREVENTION AND TREATMENT OF INFLAMMATORY BOWEL DISEASE IN MICE. INTERNATIONAL JOURNAL FOR VITAMIN AND NUTRITION RESEARCH. 2004;74:74-85.
- Mckay, D.L., Berkowitz, J.M., Blumberg, J.B., Goldberg, J.P. 2004. Communicating cardiovascular disease risk. Health Education and Behavior. 31(3):355-371.
- Kwak, H.K., Blumberg, J. 2004. Multivitamins. In: Hughes, D.A., Bendich, A. , Darlington, L.G., editors. Diest and Human Immune Function. Totowa, NJ: Humana Press, Inc. 185-202.
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Progress 10/01/02 to 09/30/03
Outputs
1. What major problem or issue is being resolved and how are you resolving it? The Dietary Antioxidants, Aging and Oxidative Stress Status CRIS is comprised of the Antioxidants Research Laboratory (ARL) and the Carotenoids and Health Laboratory (CHL). The generation of oxygen free radicals during cellular metabolism and by certain environmental factors, including lifestyle, appear to play a critical role in the aging process. High dietary intakes of antioxidant vitamins and phytochemicals are associated with better maintenance of physiologic function and a lower prevalence of many degenerative conditions in older adults. Understanding how antioxidants, especially the phytochemical carotenoids and flavonoids, reduce oxidative stress and impact the pathogenesis of chronic disease present opportunities for health promotion and alternative therapeutic modalities for an aging population. The ARL conducts studies to understand the role of dietary antioxidants, particularly
the flavonoids in conjunction with vitamins C and E, on free radical reactions and changes in oxidative stress status during aging. Lipid, protein, nucleic acid and other cellular targets of oxidative damage are assessed in experimental models and in healthy and other human populations to elucidate antioxidant requirements for optimal health. These projects contribute to the description and prediction of the impact of antioxidants and oxyradicals on age-related changes in nutrient requirements and chronic degenerative conditions. The CHL investigates dietary carotenoids and healthy aging through the following study areas: (i) The bioavailability of carotenoids (ss-carotene, lycopene, and lutein) and vitamin A equivalence of provitamin A carotenoids using intrinsically labeled spinach, collard greens, tomatoes, and carrots; (ii) The development and application of a biomarker assay of total antioxidant capacity in both the lipid and aqueous compartments of biological samples; and (iii) A
functional role of carotenoids in eye health, particularly in age-related macular degeneration. 2. How serious is the problem? Why does it matter? There is a compelling body of scientific evidence that suggests that free radical pathology is associated with many of the chronic diseases that are common among older adults, e.g., cancer, heart disease, and degenerative eye disorders such as cataracts and macular degeneration. Though not so extensively explored, several recent studies suggest antioxidants may also play a preventive or adjunctive role in conditions like arthritis, diabetes, and Parkinson's disease. However, definitive evidence is absent in all of these cases. Quantitative information linking dietary requirements for antioxidants, validated biomarkers of intermediary oxidative stress events and status, and health and aging outcomes is lacking. Such information is necessary to the development of scientifically-based recommended dietary allowances, including tolerable upper
limits of intake, for antioxidant nutrients across the lifespan and particularly for the elderly. Further, the conversion efficiency of ss- carotene to vitamin A in humans needs to be comprehensively quantified. 3. How does it relate to the National Program(s) and National Program Component(s) to which it has been assigned? Our program is directly related to the Human Nutrition Program - 107 Component 6: Health promoting properties of plant and animal foods and Component 7: Bioavailability of nutrients and food components, Priority Objective B - Conducting appropriate animal and human trials to understand nutrient bioavailability. Studies in cell cultures and animal models have demonstrated a strong relationship between the generation of oxygen free radicals and some of the pathophysiology associated with aging. In human studies, antioxidants have been demonstrated to inhibit the oxidative modification of low density lipoprotein (LDL)-cholesterol, prevent ultraviolet light-induced
damage to lens crystallins, modulate free radical damage to DNA, and enhance immune responsiveness. While these actions may underlie the efficacy of antioxidants in health promotion and disease prevention and perhaps even in the aging process, much more information is required to substantiate these relationships. The studies conducted in the ARL and CHL help to provide quantitative information necessary to the development of dietary guidelines for optimal antioxidant intakes as well as data which help describe the basic biology of the aging process. 4. What were the most significant accomplishments this past year? A. Single Most Significant Accomplishment during FY 2003: Currently available biomarkers of plasma antioxidant capacity use hydrophilic radical generators, which only produce radicals in the aqueous compartment of plasma that is made up of both aqueous and lipid compartments. The CHL has developed a novel and more comprehensive assessment of antioxidant capacity through
concomitant measurements in both the aqueous and lipid compartments of human plasma. Our studies indicate that the carotenoids and tocopherols present in these compartments are capable of removing free radicals generated in plasma and that their activity depends on the localization of the attacking radical species. Our studies also suggest that the beneficial effect of high intakes of fruits and vegetables on the risk of degenerative/chronic diseases may rely not on the effect of a single antioxidant but rather on the coordinated action of several antioxidant nutrients. B. Other Significant Accomplishment(s): B1 ARL Other Significant Accomplishments i. Consumption of nuts has been associated with a reduced risk of coronary heart disease. As the antioxidant polyphenolic compounds in nuts, found especially in their skins, may contribute to this putative benefit, we examined their bioavailability and activity in hamsters. Isorhamnetin, kaempferol, quercetin, epicatechin, and catechin
reached peak plasma concentrations at 1 h and returned to baseline by 10 h. Low density lipoprotein (LDL) collected at 1 h did not differ from baseline samples in resistance oxidation but the in vitro addition of vitamin E significantly increased lag time relative to controls. Thus, we found almond skin polyphenolics are bioavailable and work in synergy with vitamin E to protect LDL against oxidation. Ii. Observational studies suggest increased consumption of dietary flavonoids may be inversely related to risk of coronary heart disease. Dark chocolate can be a rich source of cocoa flavanols and procyanidins which have antioxidant properties and enhance endothelial nitric oxide and prostacyclin production. We conducted a clinical trial in healthy subjects randomized to receive either low or high flavonoid dark chocolate bars daily. Vascular responsiveness (endothelium-dependent flow-mediated dilation) was greater in the high vs. Low flavonoid group. Despite a marked increase in
plasma epicatechin concentrations, no significant differences were noted in the resistance to LDL oxidation, oxygen radical absorbance capacity (ORAC) values, plasma lipids or lipoproteins, blood pressure, or body weight. Thus, flavonoid-rich dark chocolate can improve endothelial function in healthy adults independent of a marked effect on biomarkers of oxidative stress. B2 CHL Other Significant Accomplishments i. Provitamin A carotenoids (principally ss-carotene) can provide vitamin A nutrition for humans, but the efficiency of production of vitamin A from dietary carotenoids is significantly less than previously calculated. The CHL investigated in vivo bioconversion of ss-carotene to vitamin A after a physiological dose of ss-carotene in oil capsules, spinach ss- carotene, or carrot ss-carotene. Our results showed that the conversion factor with oil capsules in well-nourished adults varied from 2.4 to 20.2 and the average conversion factor was 9.1 to 1 on a weight basis or 4.8 to 1 on a
molar basis; the conversion factor with spinach was 22 to 1 and with carrot carotenes was 15 to 1. These conversion factors are greater than the presently accepted 12 to 1 ratio for dietary ss-carotene to vitamin A, the factor currently used for calculating the vitamin A value of plant carotenes in the United States. ii. Meso-zeaxanthin, in addition to lutein and all-trans zeaxanthin, is another major carotenoid that makes up the macular pigment. Meso- zeaxanthin is not found in diet but may result from chemical processes occurring with in the eye. In collaboration with the Schepens Eye Research Instute, we used monkeys as a model to study macula pigment and shown that lutein is the precursor of meso-zeaxanthin. This conversion may help explain the individual variation in macular pigment response to lutein supplementation. iii. Bioavailability of dietary lutein has not been well-studied. The CHL compared the bioavailability of lutein in eggs, spinach, and supplements in healthy adult
men using carotenoid response in serum and chylomicron. We found lutein to be 3 times more bioavailable in eggs than in spinach or supplements and no differences in responses between spinach and supplements. Thus, eggs are a highly bioavailable source of lutein when compared to more conventional sources. C. Significant Activities that Support Special Target Populations: None. 5. Describe the major accomplishments over the life of the project, including their predicted or actual impact. Since 1983, research in the ARL has resulted in over 300 publications and abstracts and demonstrated the beneficial effects of dietary antioxidants through enhancing immunity, protecting the eye lens, and reducing injury during exercise. We have also helped to characterize the relationship between vitamin E and polyunsaturated fats, vitamin E-ethanol interactions, and the decline of antioxidant status with age. We have disseminated this information widely before professionals at more than 200
conferences and seminars around the world and before the general public, government regulatory agencies, and the scientific community in academia and industry, including the presentation of our data before the Institute of Medicine's Food and Nutrition Board, WHO/FAO, DHHS/USDA Dietary Guidelines Committee, DHHS Year 2000 Health Objectives Committee, Food and Drug Administration, and Surgeon General's Workshop on Health Promotion and Aging. Some of this work has resulted in the establishment of higher dietary requirements for vitamin E among older adults and a greater recognition of the role of polyphenolic antioxidants like flavonoids found in fruits, vegetables, and tea. The CHL was established in 2002 from a division within the former Gastrointestinal Nutrition Laboratory (R.M. Russell, Research Leader). The CHL has focused its studies on the bioavailability, bioconversion, antioxidant function, and tissue distribution of dietary carotenoids in humans. 6. What do you expect to
accomplish, year by year, over the next 3 years? This project is currently involved in the OSQR Panel Review Process for Human Nutrition, National Program 107. 7. What science and/or technologies have been transferred and to whom? When is the science and/or technology likely to become available to the end- user (industry, farmer, other scientists)? What are the constraints, if known, to the adoption and durability of the technology products? The research accomplishments of the ARL have been presented at several forums to research scientists, healthcare providers, and policy including: Health Supplements Information Service, London, UK; American Egg Board/Egg Nutrition Center, Amelia Is., FL; Experimental Biology, San Diego, CA; Diet and Optimal Health Conference, Linus Pauling Institute, Portland, OR; National Cancer Institute, Bethesda, MD. Scientific exchanges concerning approaches to the validation and use of biomarkers of oxidative stress have been held with several companies
and associations including: Speciality Tea Institute, Boston, MA; Tea Association Convention, Palm Springs, CA; Dole Food Company, Inc., Westlake Village, CA; Estee Lauder, Melville, NY. The research accomplishments of the CHL have been presented at several forums to research scientists, policy makers, and health journalists, including the Center for Food Safety Applied Nutrition, U. S. Food and Drug Administration; American Egg Board/Egg Nutrition Center; Korean Society for Medical Nutritional Science. 8. List your most important publications in the popular press and presentations to organizations and articles written about your work. (NOTE: This does not replace your peer-reviewed publications listed below). Several media carried stories about the work or the implications of the work carried out in the ARL, including: Print media - New York Times Magazine, Eating Well, USA Today, Remedy, Los Angeles Times, Better Homes Gardens, New York Post, Natural Health, Fitness, Essence,
Reader's Digest, Miami Herald, Kansas City Star, Prevention, Allure, Reuters Health. Websites- healthscoutnews.com, wcco.com, WebMD Medical News. Radio: KWRD, Dallas/Ft. Worth, TX and, in the United Kingdom: BFBS, LINCS, CFM, and BBC stations in Lancashire, Shropshire, Somerset. Bristol, Stoke. TV - WCVB, Boston. The following media carried reports about the work in the CHL: Tufts University Health Nutrition Letter, USDA Agricultural Research Magazine.
Impacts
(N/A)
Publications
- Blumberg, J.B. 2003. Elderly (b) nutritionally related problems. In: Caballero B., Trugo L., Ginglas P., eds. Encyclopedia Of Food Science And Nutrition, 2nd ed. Academic Press Ltd: London, 2003;2022-2027.
- Kim, Y., Ma, A.-G., Kitta, K., Fitch, S.N., Ikeda, T., Ihra, Y., Simon A.R. , Evans, T., Suzuki, Y.J. Anthracycline-induced suppression of GATA-4 transcription factor: Implication in the regulation of cardiac myocyte apoptosis. Molecular Pharmacology. 2003. v. 63. p. 368-377.
- Kitta, K., Day, R.M., Kim, Y., Torregroza, I., Evans, T., Suzuki, Y.J. Hepatocyte growth factor induces GATA-4 phosphorylation and cell survival in cardiac muscle cells. The Journal of Biological Chemistry. 2003. v. 278. p. 4705-4712.
- Suzuki,Y.J., Day, R.M., Tan, C.C., Sandven, T.H., Liang, Q., Molkentin, J. D., Fanburg, B.L. Activation of GATA-4 by serotonin in pulmonary artery smooth muscle cells. The Journal of Biological Chemistry. 2003. v. 278. p. 17525-17531.
- Milbury, P., Blumberg, J.B. 2003. Dietary antioxidants - human studies overview. In: Culter, R.G., Rodriguez H. Critical Reviews of Oxidative Stress and Aging: Advances in Basic Science, Diagnostics, and Intervention, Vol I. River Edge, NJ: World Scientific Publishing Company Inc, 2003; 487- 502.
- Ihara, Y., Suzuki, Y.J., Kitta, K., Jones, L.R., Ikeda, T. Modulation of gene expression in transgenic mouse hearts overexpressing calsequestrin. Cell Calcium. 2002. v. 32. p. 21-29.
- Milbury, P.E., Chen, C.Y., Kwak, H.K., Blumberg, J. Polyphenolics from almond skins act synergistically with alpha-tocopherol to increase the resistance of low density lipoproteins to oxidation. Free Radical Research 2002. v. 36. p. S78-80.
- Suzuki Y.J., Fanburg, B.L. Serotonin activates GATA4 transcription factor in bovine pulmonary artery smooth muscle cells. American Journal of Respiratory and Critical Care Medicine. 2002. v. 165. Abstract p. A616.
- Tang G, Qin J, Hao L, Yin S, Russell RM. Use of a short term isotope dilution method for determining vitamin A status of children. Am J Clin Nutr 2002; 76: 413-418.
- Aldini, G., Yeum, K.-J., Carini, M., Krinsky, N.I., Russell, R.M. (-)- Epigallocatechin-(3)-gallate prevents oxidative damage in both the aqueous and lipid compartments of human plasma. Biochemical and Biophysical Research Communications. 2003. v. 302. p. 409-414.
- Albert, K., Lienau, A., Krucker, M., Putzbach, K. Kohler, K. Tang, G. Investigation of Carotenoid Isomers in Biological Fluids and Tissues by Combined HPLC-MS and HPLC-NMR Analysis. PITTCON. 2003. Abstract p. 170-1.
- Connor, W., Wang, Y., Johnson, E. The tissue content of lutein and zeaxanthin in newly hatched chicks fed lutein-free and high lutein diets. Experimental Biology. 2003, v. 17:Abstract p. A757.
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Progress 10/01/01 to 09/30/02
Outputs
1. What major problem or issue is being resolved and how are you resolving it? The generation of oxygen free radicals during cellular metabolism and by certain environmental factors, including lifestyle, appear to play a critical role in the aging process. High dietary intakes of antioxidant vitamins and phytochemicals are associated with better maintenance of physiologic function and a lower prevalence of many degenerative conditions in older adults. Understanding how antioxidants reduce oxidative stress and impact the pathogenesis of chronic disease present opportunities for health promotion and alternative therapeutic modalities for an aging population. Studies in cell cultures and animal models have demonstrated a strong relationship between the generation of oxygen free radicals and some of the pathophysiology associated with aging. In human studies, antioxidants have been demonstrated to inhibit the oxidative modification of low density lipoprotein
(LDL)-cholesterol, prevent ultraviolet light-induced damage to lens crystallins, modulate free radical damage to DNA, and enhance immune responsiveness. While these actions may underlie the efficacy of antioxidants in health promotion and disease prevention and perhaps even in the aging process, much more information is required to substantiate these relationships. The Antioxidants Research Laboratory conducts studies to understand the role of dietary antioxidants on free radical reactions and changes in oxidative stress status during aging. Lipid, protein, nucleic acid and other cellular targets of oxidative damage are assessed in experimental models and in healthy and other human populations to elucidate antioxidant requirements for optimal health. Research is also focused on the role of antioxidants in signal transduction pathways to explain the molecular mechanisms of action of these dietary constituents. These projects contribute to the description and prediction of the impact of
antioxidants and oxyradicals on age-related changes in nutrient requirements and chronic degenerative conditions. 2. How serious is the problem? Why does it matter? There is a compelling body of scientific evidence that suggests that free radical pathology is associated with many of the chronic diseases that are common among older adults, e.g., cancer, heart disease, and degenerative eye disorders such as cataracts and macular degeneration. Several recent studies suggest antioxidants may also play a preventive or adjunctive role in conditions such as arthritis, diabetes, and Parkinson's disease. However, definitive evidence is absent in all of these cases. Quantitative information linking dietary requirements for antioxidants, validated biomarkers of oxidative stress, and health and aging outcomes is lacking. Such information is necessary to the development of scientifically-based recommended dietary allowances, including tolerable upper limits of intake, for antioxidant nutrients
across the lifespan and particularly for the elderly. 3. How does it relate to the national Program(s) and National Program Component(s) to which it has been assigned? This research is conducted within the National Program 107 - Human Nutrition. The studies conducted in the Antioxidants Research Laboratory help to provide quantitative information necessary to the development of dietary guidelines for optimal antioxidant intakes as well as data which help describe the basic biology of the aging process. This research is most closely related to the Human Nutrition program components "nutrient requirements" and the "relationship between diet, genetics and lifestyle and the risk for chronic disease". 4. What was your most significant accomplishment this past year? A. Single Most Significant Accomplishment during FY 2002: Many plant foods contain polyphenols, phytochemicals which possess antioxidant properties when tested in vitro. However, little is known about whether these compounds,
especially flavonoids, are well absorbed by the body and can function in vivo as antioxidants. The laboratory has tested polyphenols from almond skins, chocolate, elderberry, and oats. These polyphenols are bioavailable and can increase the resistance of LDL to oxidation, an event associated with the formation of plaque in arteries of the heart. B. Other Significant Accomplishments: 1. Polyphenols may act as antioxidants directly by quenching reactive oxygen species and indirectly by chelating transition metals. However, their interaction with the antioxidant vitamins C and E have not been carefully examined. When flavonoids are combined with vitamins E and C, even at very low levels, they act in synergy, i.e., in a fashion where the sum of their actions is much greater than each nutrient alone, to protect against LDL oxidation. This combination appears to play a co- defensive role against atherogenesis. 2. Muscle damage resulting from eccentric exercise provides a useful model of
oxyradical-induced injury and age-related responses to oxidative stress. In a randomized clinical trial of vitamin E supplementation in healthy young and older men undergoing an intense bout of downhill running, vitamin E prevented exercise-induced increases in selected measures of lipid and nucleic acid oxidation. These changes were dependent, in part, upon age. C. Significant Activities that Support Special Target Populations: None. 5. Describe your major accomplishments over the life of the project, including their predicted or actual impact? Since 1983, research in the Antioxidants Research Laboratory has resulted in over 300 publications and abstracts and demonstrated the beneficial effects of dietary antioxidants through enhancing immunity, protecting the eye lens, and reducing injury during exercise. The laboratory has also helped to characterize the relationship between vitamin E and polyunsaturated fats, vitamin E-ethanol interactions, and the decline of antioxidant status
with age. This information has been disseminated widely before professionals at more than 195 conferences and seminars around the world and before the general public,the scientific community in academia and industry, and government regulatory agencies, including the Institute of Medicine's Food and Nutrition Board, the WHO/FAO, the DHHS/USDA Dietary Guidelines Committee, the DHHS Year 2000 Health Objectives Committee, the Food and Drug Administration, and the Surgeon General's Workshop on Health Promotion and Aging. Some of this work has resulted in the establishment of higher dietary requirements for vitamin E among older adults and a greater recognition of the role of polyphenolic antioxidants like flavonoids found in fruits, vegetables, and tea. 6. What do you expect to accomplish, year by year, over the next 3 years? Year 1: 1) Complete a clinical trial on the effect of black and green tea on oxidative stress and glucose homeostasis in patients with Type 2 diabetes. 2) Complete a
pilot project and initiate a full study of the antioxidant effect of polyphenols in vivo in a rat model of vitamin E deficiency. 3) Complete a study of the effect of dietary antioxidants on aging and oxidative stress in a dog model. 4) Examine the effects of age and dietary antioxidants on the ability of rodent cardiac myocytes to mount endogenous protective responses to oxidative stress (ischemic preconditioning). 5) Explore the role of dietary antioxidants, aging, and free radicals in the maintenance heart function after ischemic preconditioning. 6) Continue a study to test whether homocysteine impacts tissue damage following acute ischemic stroke by elevating oxidative stress. 7) Complete a human study on the bioavailability, metabolism, and antioxidant capacity of polyphenol-rich extracts from almond skin and oats. Year 2: 1) Complete the study of the antioxidant effect of polyphenols in vivo in a rat model of vitamin E deficiency. 2) Complete the study on the effects of age and
dietary antioxidants on the ability of rodent cardiac myocytes to mount endogenous protective responses to oxidative stress (ischemic preconditioning). 3) Complete the project on the role of dietary antioxidants, aging, and free radicals in the maintenance heart function after ischemic preconditioning. 4) Continue the homocysteine/tissue damage following acute ischemic stroke by elevating oxidative stress study. 5) Characterize the pharmacokinetics, antioxidant capacity, and action on vascular function, especially in the retina, of polyphenols from grapes/grape seed, bilberries, and other flavonoid-rich foods in an animal model and in humans. 6) Collaborate on a study to correlate biomarkers of oxidative stress status with exercise and postprandial antecedents of diabetic complications. Year 3: 1) Complete the homocysteine/tissue damage project. 2) Continue the polyphenols/flavonoid-rich foods pharmacokinetics, antioxidant capacity, project. 3) Continue the biomarkers of oxidative
stress status with exercise and postprandial antecedents of diabetic complications project. 4) Explore the effects of dietary antioxidants on oxyradical-induced breast and colon cancers in animal models and human studies. 7. What technologies have been transferred and to whom? When is the technology likely to become available to the end user (industry, farmer other scientist)? What are the constraints, if known, to the adoption durability of the technology? The research accomplishments of this CRIS have been presented at several forums to research scientists, healthcare providers, and policy including: American College for Advancement in Medicine, Fort Lauderdale, FL; Third International Symposium on Tea and Health, Washington, DC; Fifth International Symposium on Nutraceuticals and Functional Ingredients, Geneva, Switzerland; Cargill Corporation, Minneapolis, MN; MA; Cornell University, Ithaca, NY; National Natural Foods Association, Las Vegas, NV; California Avocado Commission,
Santa Barbara, CA; Chinese Institute of Food Science and Technology, Xi'an, China; and International Life Sciences Institute, Beijing, China. Scientific exchanges concerning approaches to the validation and use of biomarkers of oxidative stress have been held with several companies and associations including the California Avocado Commission, Alcon Laboratories, Wyeth Consumer Healthcare, Quaker Oats, Almond Board of California, American Egg Board, and Tea Council of the USA. 8. List your most important publications and presentations, and articles written about your work (NOTE: this does not replace your review publications which are listed below) The following media carried stories about the work or the implications of the work carried out in the Antioxidants Research Laboratory: Print media - Natural Health Magazine, New Choices, Reuters Health, Health Scout News, Newsweek, Better Homes and Gardens, Arthritis Today, Toronto Star, New Age, USA Weekend, Bottom Line Personal, Natural
Health, Prevention, Cooking Light, Chicago Tribune, Newsday. Radio - WHNZ (Tampa, FL), WBAI (New York, NY), WNPR (Hartford, CT) TV - WCVB (Boston, MA), CBS (New York, NY). Websites - WebMD Medical News.com, Nutrition.about.com , LivingLonger. com, wnpr.org, nhionline.net, HealthScoutNews.com, TheBostonChannel.com, HealthAtoZ.com. Presentations: Jeffrey Blumberg, Ph.D. "Vitamin Supplements" - presented at the Council on Aging, Watertown, Massachusetts - January 23, 2002
Impacts
(N/A)
Publications
- Ihara, Y., Suzuki, Y.J., Kitta, K., Jones, L.R., Ikeda, T.. Modulation of gene expression in transgenic mouse hearts overexpressing calsequestrin. Cell Calcium. 2002. v. 32. p. 21-29.
- Modi, G.K., Milbury, P.E., Blumberg, J.B., Jaber, B.L., Pereira, B.J.G., Strom, J.A., Guo, D., Rao, M., Balakrishnan, V.S., King, A.J. Antioxidant therapy with alpha-tocoperhol in hemodialysis. Journal of the American Society of Nephrology. 2001. v. 12. Abstract p. A2062.
- Balakrishnan, V.S., Cendoroglo, M., King, A.J., Blumberg, J., Modi, G., Pereira, B.J.G., Jaber, B.L. Antioxidant defenses and oxidative stress in acute renal failure. Journal of the American Society of Nephrology. 2001. v. 12. Abstract p. 163A.
- Kitta, K., Day, R.M., Ikeda, T., Suzuki Y.J.. Hepatocyte growth factor protects cardiac myocytes against oxidative stress-induced apoptosis. Free Radical Biology and Medicine. 2001. v. 31. p. 902-910.
- Day, R.M., Yang Y., Suzuki, Y.J., Stevens, J., Pathi, R., Perlmutter, A., Fanburg B.L., Lanzillo, J.J. Bleomycin upregulates gene expression of angiotensin-converting enzyme via mitogen-activated protein kinase and early growth response 1 transcription factor. American Journal of Respiratory Cell and Molecular Biology. 2001. v. 25. p. 613-619.
- Blumberg, J.B., Cappellano, K. Nutraceuticals and functional foods: Phytochemical research at Tufts Nutrition. Food Technology. 2002. v. 56. p. 23.
- McKay, D.L., Blumberg, J.B. The role of tea in human health: an update. Journal of the American College of Nutrition. 2002. v. 21. p. 1-13.
- Blumberg, J.B. An update: Vitamin E supplementation and heart disease. Nutrition in Clinical Care 2002. v. 5. p. 50-55.
- Milbury, P.E., Gao, G., Prior, R.L., Blumberg, J.B. Bioavailability of elderberry anthocyanins Mechicanisms of Ageing and Development. 2002. v. 123. p. 997-1006.
- Sacheck, J.M., Blumberg, J.B., Milbury, P.E., Cannon, J.G., Roubenoff, R. Vitamin E reduces muscle damage and biomarkers of oxidative stress after exercise. FASEB Journal. 2002. v. 16. Abstract p. A1137.
- Jacob, R., Aiello, G., Stephensen, C., Blumberg, J., Milbury, P., Wallock, L., Ames, B. Moderate antioxidant supplementation has no effect on biomarkers of oxidant damage in healthy men. FASEB Journal. 2002. v. 16. Abstract p. A981.
- Milbury, P., Chen, C.-Y., Kim, C., Blumberg, J. Polyphenolics from almond skins with a-tocopherol synergistically increase the resistance of LDL to oxidation. FASEB Journal. 2002. v. 16. Abstract p. A1106.
- Chen, C.-Y., Milbury, P., O'Leary, J., Collins, F.W., Blumberg, J. Synergy between oat polyphenolics and a tocopherol in prevention of LDL oxidation. FASEB Journal. 2002. v. 16. Abstract p. A1106.
- Turner W, Milbury P, McMahon KK. Dietary grapes do not reduce progression of atherosclerosis in hyperlipidemic hyperinsulinemic mice. FASEB Journal. 2002. v. 16. Abstract p. A240.
- Clement, S.A., Tan, C.C., Guo, J., Kitta, K., Suzuki, Y. J. Roles of protein kinase C and a-tocopherol in regulation of signal transduction for GATA-4 phosphorylation in HL-1 cardiac muscle cells. Free Radical of Biology & Medicine. 2002. v. 32. p. 341-349.
- Blumberg, J.B., Hughes, D.A. Vitamins and immunocompetence. Bibliotheca Nutritio et Dieta. 2001. v. 55. p. 200-205.
- Kitta, K.R., Day, R.M., Remeika, J., Blumberg, J.B., Suzuki, Y.J. Effects of thiol antioxidants on hepatocyte growth factor signaling in cardiac myocytes. Antioxidants & Redox Signaling. 2001. v. 3. p. 911-918.
- Sacheck, J.M., Blumberg, J.B. The role of vitamin E and oxidative stress in exercise. Nutrition. 2001. v. 17. p. 809-814.
- Handelman, G.J., Walter, M.F., Adhikarla, R., Gross, J., Levin, N.W., Blumberg, J.B. Elevated plasma F2 isoprostanes in patients on long-term hemodialysis. Kidney International 2001. v. 59. p. 1960-1966.
- Kitta, K., Clement, S., Remeika, J., Blumberg, J.B., Suzuki, Y.J. Endothelin-1 induces phosphorylation of GATA 4 transcription factor in HL- 1 atrial muscle cell line. The Biochemical Journal. 2001. v. 359. p. 375- 380.
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Progress 10/01/00 to 09/30/01
Outputs
1. What major problem or issue is being resolved and how are you resolving it?
The generation of oxygen free radicals during cellular metabolism and by certain environmental factors, including lifestyle, appear to play a critical role in the aging process. High dietary intakes of antioxidant vitamins and phytochemicals are associated with better maintenance of physiologic function and a lower prevalence of many degenerative conditions in older adults. Understanding how antioxidants reduce oxidative stress and impact the pathogenesis of chronic disease present opportunities for health promotion and alternative therapeutic modalities for an aging population. The Antioxidants Research Laboratory conducts studies to understand the role of dietary antioxidants on free radical reactions and changes in oxidative stress status during aging. Lipid, protein, nucleic acid and other cellular targets of oxidative damage are assessed in experimental models and in healthy and other human populations to elucidate antioxidant requirements for optimal health. Research is also
focused on the role of antioxidants in signal transduction pathways to elucidate the molecular mechanisms of action of these dietary constituents. These projects contribute to the description and prediction of the impact of antioxidants and oxyradicals on age-related changes in nutrient requirements and chronic degenerative conditions.
2. How serious is the problem? Why does it matter?
Studies in cell cultures and animal models have demonstrated a strong relationship between the generation of oxygen free radicals and some of the pathophysiology associated with aging. This research suggests that free radical pathology is associated with many of the chronic diseases that are common among older adults, e.g., cancer, heart disease, and degenerative eye disorders such as cataracts and macular degeneration. In human studies, antioxidants have been shown to inhibit the oxidative modification of LDL-cholesterol, prevent ultraviolet light-induced damage to lens crystallins, modulate free radical damage to DNA, and enhance immune responsiveness. Though not so extensively explored, several recent studies suggest antioxidants may also play a preventive or adjunctive role in conditions such as arthritis, diabetes, and Parkinson's disease. While these actions may underlie the efficacy of antioxidants in health promotion and disease prevention and perhaps even in the aging
process, much more information is required to substantiate these relationships. Quantitative information linking dietary requirements for antioxidants, validated biomarkers of intermediary oxidative stress, and health and aging outcomes is lacking. This information is necessary to develop scientifically-based recommended dietary allowances, including tolerable upper limits of intake, for antioxidant nutrients across the lifespan and particularly for the elderly.
3. How does it relate to the National Program(s) and National Component(s)?
The studies conducted in the Antioxidants Research Laboratory help to provide quantitative information necessary to the development of dietary guidelines for optimal antioxidant intakes as well as information which helps describe the basic biology of the aging process. This research relates to the Human Nutrition Program NP 107 component "nutrient requirements."
4. What were the most significant accomplishments this past year?
A. Single Most Significant Accomplishment during FY 2001: Inadequate micronutrient intake among older adults is common as is the use multivitamin supplementation. However, little information is available concerning the benefits of this behavior. A randomized clinical trial of multivitamin supplementation among 80 healthy people aged 50-87 years in the Boston area was conducted. Compared to placebo, the treatment resulted in significant increases in plasma vitamins B6, B12, C, D, E, folic acid, and riboflavin but not vitamins A and thiamin. The multivitamin reduced plasma homocysteine and prevalence of the suboptimal status of vitamins B12, C, and E. B. Other Significant Accomplishments: 1. One approach to using biomarkers of lipid peroxidation to predict the risk of chronic disease is to compare values between healthy and ill subjects. Plasma F2-isoprostanes, biomarkers of lipid peroxidation, were measured in patients with end stage renal disease on hemodialysis and
age/gender-matched healthy adults. Despite similar vitamin E status, patients had higher F2-isoprostanes, a parameter which correlated with plasma C-reactive protein, a measure of inflammation. 2. Undernutrition among the elderly contributes to their poor health outcomes after hospital discharge. A pilot study of the impact of home- delivered, nutrient-dense, prepared meals to 25 geriatric patients discharged with low serum albumin, an indicator of poor nutritional status, was conducted. The results showed significantly increased albumin status and suggested a reduced risk of rehospitalization for up to two months post-discharge. C. Significant accomplishments/activities that support special target populations: N/A
5. Describe the major accomplishments over the life of the project including their predicted or actual impact.
Since 1983, research in the Antioxidants Research Laboratory has resulted in over 290 publications and abstracts and demonstrated the beneficial effects of dietary antioxidants through enhancing immunity, protecting the eye lens, and reducing injury during exercise. We have also helped to characterize the relationship between vitamin E and polyunsaturated fats, vitamin E-ethanol interactions, and the decline of antioxidant status with age. We have disseminated this information widely before professionals at more than 190 conferences and seminars around the world and before the general public, government regulatory agencies, and the scientific community in academia and industry, including the presentation of our data before the Institute of Medicine's Food and Nutrition Board, WHO/FAO, DHHS/USDA Dietary Guidelines Committee, DHHS Year 2000 Health Objectives Committee, Food and Drug Administration, and Surgeon General's Workshop on Health Promotion and Aging. Some of this work has
resulted in the establishment of higher dietary requirements for vitamin E among older adults and a greater recognition of the role of polyphenolic antioxidants like flavonoids found in fruits, vegetables, and tea.
6. What do you expect to accomplish, year by year, over the next 3 years?
2002: (1) Complete a clinical trial on the effect of green tea on oxidative stress and glucose homeostasis in patients with Type 2 diabetes. (2) Initiate a study of the antioxidant effect of polyphenolic compounds from bilberries and oats in a rat model of vitamin E and selenium deficiency. (3) Collaborate on a study of the effect of dietary antioxidants on aging and oxidative stress in a dog model. (4) Continue to examine the effects of age and dietary antioxidants on the ability of rodent cardiac myocytes to mount endogenous protective responses to oxidative stress (ischemic preconditioning). (5) Explore the role of dietary antioxidants, aging, and free radicals in the maintenance of heart function after ischemic preconditioning. (6) Collaborate on a study to test whether homocysteine effects tissue damage following acute ischemic stroke by elevating oxidative stress. (7) Determine the bioavailability, metabolism, and antioxidant capacity of almond bran polyphenols in humans. 2003:
Complete projects (2) and (3) and continue projects (4)-(6). (8) Characterize the pharmacokinetics, antioxidant capacity, and action on vascular function of polyphenols from grapes/grape seed, bilberries, and other flavonoid-rich foods in humans. (9) Test the effects of dietary antioxidants on preconditioning-induced cardioprotection against ischemia- reperfusion injury (coronary artery ligation) and apoptosis in young and old mice. (10) Collaborate on a study to correlate biomarkers of oxidative stress status with exercise and postprandial antecedents of diabetic complications. 2004: Complete project (4) and (5) and continue projects (8)-(10). (11) Explore the effects of dietary antioxidants on apoptosis and the kinetics of depolarization-induced calcium release and activation of transcriptional pathways in rat cardiac cells.
7. What science and/or technologies have been transferred and to whom? When is the science and/or technology likely to become available to the end user (industry, farmer, other scientists)? What are the constraints if known, to the adoption & durability of the technology product?
The research accomplishments of this CRIS have been presented at several forums to research scientists, healthcare providers, and policy makers including: the American Association of Retired Persons (AARP), Alexandria, VA; The Forsyth Institute, Boston, MA; FASEB Summer Research Conference, Tucson, AZ; American College of Sports Medicine, Baltimore, MD; Second International Conference on Oxidative Stress and Aging, Maui, HI; Diet and Optimum Health, Portland, OR; Fourth International Symposium on Nutraceuticals and Functional Ingredients, Geneva, Switzerland; Food 2000, Rome, Italy; Environmental Health Sciences Center, University of Wisconsin, Madison, WI; International Congress of Nutrition, Vienna, Austria; National Institute of Environmental Health Sciences, Research Triangle Park, NC; Ninth Annual Conference on Women's Health & Gender- Based Medicine, Washington, DC; Experimental Biology '01, Orlando, FL; American Oil Chemists Society, Minneapolis, MN; Association of American
Veterinary Medicine, Orlando, FL; and the American Aging Association, Boston, MA. Scientific exchanges concerning approaches to the validation and use of biomarkers of oxidative stress have been held with several companies and associations.
8. List your most important publications in the popular press (no abstracts) and presentations to non-scientific organizations and articles written about your work (NOTE: this does not replace your peer-reviewed publications which are listed below)
The following media carried stories about the work or the implications of the work conducted in the Antioxidants Research Laboratory: Print media - Wall Street Journal, Family Circle, Los Angeles Times, Washington Post, Environmental Nutrition, Bottom Line Personal, Washington Post, Family, New Choices, New York Post, Los Angeles Times, Natural Health Magazine. National Radio - NPR, CBC (Canada). Websites - healthscout.com, dietsmart.com, MaryKaye.com, health-news.co.uk, Yahoo!news.com, CBSHealthWatch. com, and Reuters.com
Impacts
(N/A)
Publications
- Blumberg, J.B. Free radical theory of aging. Morley, J.E., Armbrecht, H.J., Coe, R.M., Vellas, B., editors. SERDI Publishers, Paris/Springer Publishing Co. New York, NY. The Science of Geriatrics. 2000. p. 57-74.
- Moeller, S.M., Jacques, P.F., Blumberg, J.B. The potential role of dietary xanthophylls in cataract and age-related macular degeneration. Journal of the American College of Nutrition. 2000. v. 19(5). p. 522S-527S.
- McKay, D.L., Wilson, J., Martin, C., Boudet, K.L., Blumberg, J.B., Holay, S. The impact of home delivered meals on serum albumin and rehospitalization among elderly patients: A pilot study. Care Management. 2000. v. 6. p. 32-36.
- Couris, R.R., Tataronis, G.R., Booth, S.L., Dallal, G., Blumberg, J.B., Dwyer, J.T. Validation of a self-assessment instrument to determine daily intake and variability of dietary vitamin K. Journal of the American College of Nutrition. 2000. v. 19. p. 801-806.
- Suzuki, Y.J., Fitch, S.N., Claridad, K., Kim, Y., Blumberg, J.B. Anthacycline-induced cardiac myocyte apoptosis: Roles of NF-kB and GATA-4 in regulation of bcl-x gene expression. American Journal of Respiratory Critical Care and Medicine. 2001. v. 163. p. A462.
- Cannon, J., Blumberg, J.B. Acute phase immune response in exercise. Sen, C.K., Packer, L., Hanninen, O., editors. Elsevier Science Publishers, BV. Amsterdam. Handbook of Oxidants and Antioxidants in Exercise. 2000. p. 177-193.
- Blumberg, J.B. HOPE: Vitamin E supplementation and cardiovascular events in high risk patients. Nutrition in Clinical Care. 2000. v. 3. p. 133.
- Handelman, G.J., Adhikarla, R., Blumberg, J.B., Walter, M.F., Ronco, C., Levin, N.W. Oxidative stress in ESRD patients: Elevated plasma F2- isprostanes and correlated plasma C-reactive protein. Journal of the American Society of Nephrology. 2000. v. 11. Abstract p. 271A.
- Suzuki, Y.J., Kitta, K., Remeika, J., Day, R.M., Blumberg, J.B. Thiol antioxidants delays hepatocyte growth factor activation of MAP kinase in cardiac myocytes. FASEB Journal. 2000. v. 14(4). Abstract p. A1454.
- Kitta, K., Blumberg, J.B., Suzuki, Y.J. Biothiols modulate cell signaling for GATA-4 phosphorylation in cardiac myocytes. Biophysical Journal. 2001. v. 80. Abstract p. 582a.
- Suzuki, Y.J., Fitch, S.N., Blumberg, J.B. Daunorubicin modulates NF-kB and GATA-4 activities in cardiac myocytes. Biophysical Journal. 2001. v. 80. Abstract p. 582a.
- Blumberg, J.B. Antioxidant vitamins: the state-of-the-science. Journal of Women's Health & Gender-Based Medicine. 2001. v. 10. Abstract p. 396.
- Sacheck, J.M., Milbury, P., Walter, M.F., Blumberg, J.B., Roubenoff, R. The effect of eccentric exercise on acute-phase response oxidative stress and cytokines in young and elderly men. FASEB Journal. 2001. v. 15(5). Abstract p. A417.
- Kitta, K., Clement, S.A., Remeika, J., Suzuki, Y.J. Calcium-independent activation of GATA-4 transcription factor in cardiac myocytes. Biophysical Journal. 2001. v. 80. Abstract p. 26a.
- Clement, S.A., Suzuki, Y.J. PMA induces hyperphosphorylaton of GATA-4 transcription factor in cardiac myocytes. Biophysical Journal. 2001. v. 80. Abstract p. 582a.
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