1a. Objectives (from AD-416)
LAB: NUTRITIONAL IMMUNOLOGY 1. Determine the effect and mechanisms of food components and their interaction with age on immune function and infectious diseases. tamin E. a) Determine the mechanisms of Vitamin E-induced enhancement of T cell function in the aged with focus on early activation signaling and membrane related events. b) Determine the contribution of polymorphisms at cytokine genes to heterogeneity of vitamin E-induced effects on cytokine production and resistance to respiratory infections. 2. Determine the effect of reducing caloric intake on the immune response of humans. 3. Determine the effect and mechanisms of food components and their interaction with age on immune function and infectious diseases. LAB: VASCULAR BIOLOGY 1. Identify bioactive food components and food patterns that inhibit atherosclerosis and angiogenesis using cell culture and animal models under the following sub-objectives: a) Determine bioavailability of avenanthramides from oats and characterize their potency and molecular mechanism of inhibition of vascular smooth muscle cell proliferation using cell culture systems and the femoral artery injury mouse model. b) Elucidate the molecular mechanism of catechins and curcumin and other dietary bioactive compounds on the inhibition of angiogenesis associated with adipose tissue growth and obesity. c) Determine the comparative bioavailability and biopotency of tocopherols versus tocopheryl phosphate on the inhibition of femoral artery injury model of vascular atherosclerosis and restenosis. 2. Determine the anti-inflammatory and anti-proliferative effects of avenanthramides of oats and derivatives on several colonic cancer cells lines and mouse models of inflammatory bowel disease and colon cancer.
1b. Approach (from AD-416)
LAB: NUTRITIONAL IMMUNOLOGY T cell function declines with age resulting in higher incidence of infections in the elderly. We showed that vitamin E (E) supplementation enhances T cell function in the aged. In Objective 1-A, we will test the hypothesis that T cell receptor (TCR)-induced signalosomes (combination of protein and lipids that are formed at the site of T cell and antigen presenting cells) exhibit age- and vitamin E (E)-related differences in their patterns of protein and lipid recruitment. We will identify qualitative and quantitative age- and E-related differences in the protein and lipid composition of signalosomes using an enhanced magnetic immunoisolation procedure and highly sensitive and quantitative proteomics and lipidomics methods. In objective 1-B, we will test the hypothesis that higher frequencies of specific cytokine polymorphisms contribute to incidence and severity of respiratory infection (RI) in the aged and that the effect of E on RI is dependent on cytokine genotype. This will be tested using data and DNA samples collected from a 1-year randomized, double-blind, controlled (RTC) study of E supplementation in elderly. In Objective 2 we will test the hypothesis that a long- term calorie restriction (CR) intervention in humans will enhance T cell-mediated function and that the CR- mediated effect is due to intrinsic changes in T cells and/or a reduction in prostaglandin PGE2 production. This hypothesis will be tested utilizing subjects enrolled in the NIA- supported multi-center RTC, CALERIE Phase 2 and determining the effect of CR on T cell subsets proliferation, and intra- and extra-cellular cytokine, and PGE2 levels before, and following 1 and 2 years of 25% CR. These studies will help develop effective strategies to improve the immune response in the elderly. LAB: VASCULAR BIOLOGY The main objective of this project plan is to determine bioavailability, potency and mechanism of action of several bioactive food components, including avenanthramides (Avns) of oats, curcumin of turmeric, catechins of green tea and isomers of tocopherol in the prevention of atherosclerosis and angiogenesis as they relate to CVD, obesity and cancer. Specifically, we will determine bioavailability of Avns from oats and characterize their potency and mechanism of inhibition of vascular smooth muscle cell proliferation using cell culture and the femoral artery injury mouse model. Further, we will investigate the anti-inflammatory and anti-proliferative effects of Avns of oats and derivatives on several cancer cells lines and mouse models of inflammatory bowel disease and colon cancer. We will also elucidate the molecular mechanism of catechins and curcumin and other dietary bioactive compounds on the inhibition of angiogenesis associated with adiposity and obesity. We also plan to investigate the comparative biopotency of' alpha-tocopherol (alpha-T) versus alpha-tocopheryl phosphate (alpha-TP) on the inhibition inflammatory cytokines and monocyte adhesion in cell culture systems and on comparative bioavailability and efficacy of alpha-T vs. alpha-TP on femoral artery injury model of atherosclerosis.
3. Progress Report
This project includes the work of two subordinate projects at the HNRCA funded through a Specific Cooperative Agreement with TUFTS UNIVERSITY. For further information and progress reports, see 1950-51000-067-01S (Nutrition, Aging, Immune and Inflammatory Responses in Health and Diseases) and 1950-51000-067-02S (Bioactive Food Components and Modulation of Atherosclerosis and Angiogenesis).
1. Vitamin E and respiratory infection (RI). (LAB: Nutritional Immunology). Vitamin E has been shown to improve immune response that helps reduce risk of RI in the elderly. However the effectiveness of vitamin E supplementation varies among the individuals. ARS-funded researchers at Tufts University in Boston, MA, found that one reason for different responses to vitamin E is that there is a small genetic variation in the genes directing synthesis of cytokines (protein molecules involved in regulating immune cell function). This small variation among individuals makes them respond differently to vitamin E supplementation and the way in which their bodies defend against infection. This result suggests that we need to develop a "customized" rather than a universal recommendation for vitamin E in order to gain optimum benefit from nutritional supplementation with this nutrient.
2. Tocotrienols improve immune function in old mice. (LAB: Nutritional Immunology). Alpha-tocopherol (alpha-Toc), the most well-known member of vitamin E family, has been shown to improve age-related decline in immune function. Another member of the vitamin E family, tocotrienols, are not as well known and are studied less compared to alpha-Toc. Specifically,their ability to affect immune cell function was unknown. ARS-funded researchers at Tufts University in Boston, MA, demonstrated that tocotrienol supplementation also improves immune response in old mice. They also learned that the different tocotrienols have varying strengths and safety dose ranges. This study has identified a new potential health benefit for lesser known members of the vitamin E family. This information can be used to optimize the diet of older adults to boost their immune response against microbes and cancers.
3. Anti-obesity and anti-atherosclerotic effect of curcumin in turmeric. (LAB: Vascular Biology). Curcumin is known for its anti-inflammatory and anti-cancer activity. ARS-funded researchers from Tufts University, Boston MA have established in an animal model that curcumin, a bioactive component in turmeric spice, can prevent body weight gain. This is done through increasing burning of body fat and by suppressing growth of new blood vessels in fat tissue. In addition, we found that curcumin at low doses, not high doses, is effective at reducing vascular injury in a susceptible mouse model that has been fed Western style high fat diet. The anti-obesity effect of curcumin is a significant finding in relation to dietary factors that can help reduce the epidemic of obesity.
Ahmed, T., Das, S., Golden, J.K., Saltzman, E., Roberts, S.B., Meydani, S.N. 2009. Calorie restriction (CR) enhances T cell mediated immune response in overweight men and women. Journal of Gerontology. 64:1107-1113.