1a. Objectives (from AD-416):
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.
1b. Approach (from AD-416):
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, doubleblind, 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.
3. Progress Report:
Zinc is essential for the regulation of immune response. We previously reported that 30% of nursing home elderly had low serum zinc levels, and zinc deficiency was significantly associated with higher incidence and duration of pneumonia, as well as decreased all-cause mortality. We have now determined the effect of zinc supplementation on serum zinc levels and T-cell mediated function (a key cell in fighting against pathogens, the function of which declines with age) in the zinc deficient nursing home elderly. We found that dietary supplementation with 30 mg/day of zinc for 3 months is effective in increasing serum zinc levels and improving T-cell mediated function. Results suggest that zinc supplementation may be an effective strategy to improve immune function in zinc deficient nursing home elderly. Obese individuals and the elderly are at a high risk of becoming iron deficient and having an impaired immune system. Little is known about the effect of obesity in the elderly on iron status and immune response. Weight loss through calorie restriction may have beneficial effects on iron status and immune response of obese young and older adults. We have shown that elderly Ecuadorian women with high BMI have higher inflammation and increased hepcidin, a hormone that when upregulated, lowers iron levels in blood. We have also shown, in collaboration with researchers at Boston University School of Medicine, that calorie restriction in obese adults lowers inflammation and hepcidin. In this study we also showed that macrophages in the subjects’ adipose tissue may be significant producers of hepcidin, which might be part of the mechanism by which iron deficiency occurs in the obese. Currently, we are investigating the impact of calorie restriction on iron homeostasis and immune response of young and older obese women in. With this research we hope to elucidate the mechanisms underlying impairment of iron status and immunity in young and older obese individuals, with the long term goal of developing strategies for their improvement. Some components in olive oil, referred to as phenolic compounds, have been shown to have antioxidant and anti-inflammatory properties. Very few studies have evaluated the role of olive oil, the main oil consumed as part of the Mediterranean diet, on immune function of the elderly. We are conducting a study to determine whether high olive oil consumption will reduce inflammation and improve cell-mediated immune response in the healthy elderly (aged 65 and above). Measures of interest include the in vivo immune response index, delayed type hypersensitivity skin response and the ex vivo immune response indices such as immune cell counts in blood, proliferative response of T lymphocytes and their subsets, and production of different cytokines known to regulate immune and inflammatory responses. The study is designed to have 20 participants in each diet group (olive oil or control) when completed. Currently, of the 44 eligible participants, 17 have completed the study, 6 are currently in the study, and 17 have been scheduled to start the study. Results have the potential to identify olive oil consumption as a dietary intervention to favorably modulate immune and inflammatory responses, which has the implication of preventing and/or mitigating age-related diseases. Observational studies have suggested an association of whole grain diet with reduced risk of developing obesity, diabetes, heart disease, and certain cancers. We are conducting a study to determine how consumption of diets rich in whole grains vs. diets rich in refined grains would impact immune, digestive, and cardiovascular health in the healthy adults aged 45-65 years. In this study, we plan to have 40 participants in each of the two diet groups. Currently, 7 participants have started, and 12 are scheduled to start the study. Results have the potential to identify whole grains as a dietary intervention to improve physiological functions in multiple bodily systems. We have conducted a study to determine the effect of two years of calorie restriction (CR) on immune response in humans. We have completed all the participant visits, sample collections, and measurements for proposed analytes. The data analyses are underway, and the final data report will be submitted to the collaborators at Duke University. When completed, this work will provide the first data to learn how long term CR impacts human immune response. To quantify more precisely the measurement errors associated with different methods for assessing diet and physical activity in large epidemiologic studies, the Nutritional Immunology Laboratory collaborated with the Harvard School of Public Health to conduct the Women’s Lifestyle Validation Study (WLVS) and the Men’s Lifestyle Validation Study (MLVS). Through the use of multiple measurements, the studies will evaluate the validity of various objective biomarkers, as well as existing and new methods for assessing diet and physical activity. Over a period of one year, WLVS has successfully collected data on 761 women among participants in the ongoing Nurses’ Health Study I (NHS I) and Nurses’ Health Study II (NHSII) cohorts. Laboratory determinations of study samples, data cleaning and preliminary analyses of available data are currently ongoing. MLVS has successfully enrolled about 400 participants from the Health Professionals Follow-Up Study and the Harvard Pilgrim Health Care, and aims to enroll 300 more. Findings from the two studies will be of great value for the interpretation of a large body of published literature on the impact of diet on health and immune response in older men and women, as well as inform future study design and methods. Little is known about the impact of age on asthma despite the increasing occurrence of the disease in elderly patients. In addition to investigating the role age plays in this disease, we also looked at the efficacy of a potential preventative dietary component: fish oil. We found that fish oil was effective at decreasing both the tissue damage caused by asthma and reducing the number of inflammatory cells in the lungs of old asthmatic mice. Although more research is necessary, these results provide support for identifying new ways to mitigate asthma in elderly. Over activity of T cells is a key contributor to autoimmune disease, the incidence of which increases with age. Green tea has components in it that are biologically active and can affect T cells. One such component is epigallocatechin gallate or EGCG, which inhibits T cell proliferation and function. We investigated the effect of EGCG on several protein molecules [interleukin (IL)-2, IL-7, and IL15], which are known to transmit signals to maintain and regulate T cell growth and function, as well its underlying mechanisms. We found that EGCG interfered with the interaction of these molecules with their receptors, the structures on cell surface that receive these molecules and relay signals into the cells, by reducing their production and availability. EGCG can thus block signal transmission to T cells resulting in reduced T cell activation. These results identify EGCG as a potential dietary intervention to suppress the overactive response of T cells that causes autoimmune diseases. It is believed that various T cells play an important role in the autoimmune response. We have previously reported that EGCG can improve autoimmune disease in an animal model. The underlying mechanism for this effect of EGCG is not completely understood. One mechanism through which EGCG could improve autoimmune disease is by altering the population of different types of T helper (Th) cells. To further determine the mechanisms, we investigated how EGCG modulates generation of various Th cells from a common precursor, called naïve T cells. We found that EGCG reduced development of naïve T cells into autoimmune-promoting Th cells (Th1, Th9, and Th17), and protected the positive response of the T cells known as regulatory T cells, a type of T cells critical in suppressing autoimmune response. We further found that EGCG affected the regulatory network for each of the T cell types. These results as well as those mentioned above will help in better understanding of EGCG’s beneficial effect on autoimmune diseases and provide useful information for potential application in the prevention of autoimmune diseases in humans. Wolfberry (WB) has been demonstrated to improve immune response against the influenza infection in old mice. Our preliminary results indicated that wolfberry could improve antibody response against influenza virus in old mice. To determine the underlying mechanisms, we investigated the impact of wolfberry on dendritic cells(DC), a key cell involved in helping B cells produce antibodies. The DC from old mice were treated with WB in vitro, and their ability to affect DC function was determined. We found that WB promoted DC maturation of DC and enhanced their function as indicated by production of regulatory molecules. All these processes are important for recognizing pathogens and developing antibodies to combat pathogens. These results suggest that WB may improve the ability of DC in the elderly to induce antibody production. Further studies are needed to determine if similar results can be reproduced in humans.
1. 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, Massachusetts, 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. 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, MMassachusetts, 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.