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. 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, animal models and human subjects 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 progress report included 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 atherscierosis and angiogensis).
1. LAB: Nutritional immunology: Wolfberry (Goji berry) consumption enhances defense against influenza infection. Flu is a major cause of illness and death worldwide. Improving immune function is a key to increase a host’s resistance to influenza infection, and nutritional intervention is a promising approach to attaining this goal. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, MA, conducted a study to determine the effect of wolfberry, a wild fruit shown to boost immune response, on influenza infection in an animal model. They found that wolfberry consumption reduced morbidity due to influenza infection as exhibited by prevention of influenza-induced weight loss and pathological changes in the lungs. Further they showed that these effects of wolfberry were due to maintaining optimal immune response during infection. These results strongly suggest that wolfberry would have the potential to improve the immune response and increase resistance to influenza infection in older humans.
2. LAB: Nutritional immunology: Obesity in pregnancy impairs fetal iron status. Iron is essential for fetal development. Since obese individuals are at risk of becoming iron deficient, it is important but yet not known whether obesity in pregnancy would affect maternal and fetal iron status. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, MA, conducted a study to find the answers. They showed that cord blood from newborns of obese mothers had significantly lower levels of iron than cord blood of newborns born from lean mothers. The obese women also had significantly higher blood levels of inflammation markers and hepcidin, a molecule known to regulate iron homeostasis. These findings suggest that maternal obesity may compromise iron transfer to fetus, which poses a potential, negative impact on the offspring development and long-life health status.
3. LAB: Vascular biology: Consumption of curcumin, a bioactive component of turmeric spice, may reduce heart disease. Eating a diet high in fat induces obesity and increases risk of heart disease, which can be prevented to some extent by consuming foods that contain certain natural substances. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, MA, investigated the effect of consuming curcumin, a compound present in turmeric and curry spices, on body weight gain, obesity and heart disease in animal model of heart disease. They found that curcumin suppressed body fat and body weight gain and reduced several risk factors for heart disease and diabetes. These observations in animal models provide a platform to translate their findings to humans.
4. LAB: Vascular biology: Curcumin reduces fatty liver. The accumulation of fat deposits in the liver caused by a high fat diet is associated with chronic inflammation, which provides an environment for the potential development of liver dysfunction and cancer. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, MA have found that supplementing Western style high fat diet in laboratory mice with increasing doses of curcumin of turmeric spice reduced the formation of fatty liver. This finding suggests that consumption of turmeric may reduce the risk of liver cancer.
5. LAB: Vascular biology: Newly discovered form of vitamin E (aTP) alters genes. One of the natural forms of vitamin E (alpha-TP), has recently been shown to be a biologically active form of vitamin E. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, MA, compared the alpha-TP form with regular vitamin E. They have found that alpha-TP may be more effective than regular vitamin E to activate certain genes that are important for blood vessel formation. This indicates that alpha-TP may help wounds to heal more quickly.Zingg, J., Hasan, S., Cowan, D., Ricciarelli, R., Azzi, A., Meydani, M. 2012. Regulatory effects of curcumin on lipid accumulation in monocytes/macrophages. Journal of Cellular Biochemistry. 113:833-840.