1a. Objectives (from AD-416)
1. Investigate the molecular and cellular basis of age-related decline in T cell function and its reversal by vitamin 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.
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
In fiscal year 2009-2010 we made progress toward all 3 objectives. 1-In investigating the molecular mechanisms of age-related decline in T cell function (cells involved in fighting against infection and cancer), we demonstrated that both T cell membrane and immune synapse [complexes formed between T cells and an antigen presenting cells that represent the first step in defensive activation of T cells against pathogens (IS)] of aged T cells have significantly higher levels of special classes of lipids, sphingomyelins and ceramides, than young T cells. Since sphingolipids are implicated in T cell activation and function, age-dependent changes in the sphingolipid species retained in IS could influence T cell activation and function and may contribute to functional T cell defects in the aged. 2-Vitamin E affects immune and inflammatory responses but there is great variability among individuals and their response to vitamin E supplementation. We demonstrated that this is partly due to the genetic difference as determined by using functional nucleotide polymorphisms (SNPs) at genes related to immune response against infection. For example, effect of vitamin E on tumor necrosis factor (TNF)-a (an inflammatory cytokine) production is dependent on the TNF-a genotype. Vitamin E effectively reduced the production of this inflammatory cytokine in individuals who had the TNF-a genotype that pre-disposes them to higher inflammation only. These results have implications for vitamin E dietary recommendation. 3-In the ongoing study to determine the effect of two years of calorie restriction (CR) on immune response in humans, we have collected samples from 67 subjects. We have completed sample collection for all three phases (baseline, year 1, and year 2) for 8 subjects, and two phases (baseline and year 1) for 32 subjects. Data analyses from 24 subjects have been completed and submitted to our collaborators at Duke Clinical Research Institute. When completed, this work will generate the first data on long-term impact of CR on the human immune response. 4-Both natural and synthetic forms of vitamin E are used by the public and scientists interested in health benefits of this vitamin E. We demonstrated significant qualitative and quantitative differences between the two forms of vitamin E in regulating gene expression in T cells. Furthermore, we have identified unique biological markers for supplementation with each form of vitamin E. 5-Zinc deficiency is associated with reduced immunity and higher risk of pneumonia in the elderly. Double-blind, placebo controlled clinical trials are needed to demonstrate efficacy of zinc supplementation in reducing pneumonia risk in elderly. We conducted a pilot study in nursing home elderly (NHE) to determine if supplementation with 30 mg/day of zinc improved serum zinc level and immune response in NHE. Zinc supplementation (30 mg/d zinc) for 3 months significantly increased serum zinc levels compared to the placebo group (5 mg/d zinc). This result will be used in planning future studies to determine efficacy of zinc supplementation in reducing incidence of pneumonia in NHE. For publications see project 1950-51000-067-00D.
1. Vitamin E and respiratory infection (RI). 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 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. 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 (T3), 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 demonstrated that T3 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.