Location: Jean Mayer Human Nutrition Research Center On Aging
2024 Annual Report
Objectives
Objective 1: Determine the effect of nutritional intervention such as vitamin E on immune and inflammatory responses and resistance to infection using appropriate human and animal models.
Sub-objective 1A: Establish the effects of vitamin E supplementation on the incidence and severity of human rhinovirus infection in healthy community dwelling older adults.
Sub-objective 1B: Understand the mechanistic basis for vitamin E-mediated changes in incidence and severity of common cold.
Objective 2: Determine the life-long effect and underlying mechanisms of food components such as fruits and vegetables on life and health span through longitudinal intervention trials using appropriate animal models.
Sub-objective 2A: Determine the effect of long term fruit and vegetable consumption on key biological functions, pathologies, and median life span in lean and obese mice.
Sub-objective 2B: Determine the underlying mechanism of fruit and vegetable impact on life- and health-span in normal weight and obese mice.
Approach
Aging is associated with dysregulation of immune and inflammatory responses, which contribute to higher morbidity and mortality from several infectious and non-infectious chronic diseases associated with aging. Nutritional status, through maintaining healthy metabolic activity, and immune and inflammatory responses, is a key factor in enhancing health- and life-span. Our long-term goal is to determine the underlying mechanisms of age-related immune and inflammatory dysregulation in order to develop nutritional interventions to prevent/reduce these alterations. Objective 1 will determine the impact and underlying mechanisms of vitamin E on human rhinovirus (HRV)-induced infection (common cold) utilizing a double-blind, randomized, placebo-controlled trial in healthy community-dwelling older adults. Efficacy of vitamin E will be assessed following exposure to HRV by disease incidence and severity, viral shedding, anti-viral immune response, oxidative stress, and expression of signature genes. Objective 2 will determine effect of long-term consumption of fruits and vegetables on median life-span and key immune and metabolic functions at different life stages in an animal model (normal weight and obese mice). Both longitudinal and cross-sectional design will be used to gain insight into causaul relationship between increasing fruits and vegetable consumption and promotion of health- and life-span. Mechanistic investigation will focus on inflammation, oxidative stress, sphingolipid (particularly ceramide) metabolism, and gut microbiota. The results generated from these studies will help develop effective nutritional strategies to delay/mitigate age-related diseases leading to increased health- and life-span.
Progress Report
A. The safety of novel forms of iron in healthy, iron-replete adults has been questioned since some observations suggest they may increase the susceptibility to malaria infection. As part of Objective 1, we therefore tested the hypotheses that supplementation with two novel forms of iron are safe as indicated by susceptibility to malarial infection, bacterial infectivity, and gut irritation compared to a conventional form of iron supplementation. Two phases of randomized, double-blinded trials were conducted. Supplementation with any form of iron did not affect any primary endpoint. In regard to symptoms of gut irritation, there were inconsistent findings between the two phases of the study and no form of iron consistently fared worse. In summary, few differences were found between groups in the primary endpoints, indicating that 28 days of any form of iron may be safe for healthy, iron-replete adults.
B. Pneumonia is a major public health problem for older adults, being one of the leading causes of hospitalization and death, particularly for elderly nursing home residents. We previously conducted a clinical trial in which we demonstrated that 29% of nursing home residents had low serum zinc levels coinciding with a two-fold increase in pneumonia incidence and duration in comparison to individuals with adequate serum zinc levels. However, causality could not be inferred and necessitates a double-blind clinical trial. To determine the appropriate supplementation dose for such a trial, as part of Objective 1, we are conducting a randomized, placebo-controlled, double-blind clinical pilot trial aimed at delineating the optimal dosage (30 and 60 mg/day elemental Zn) and establishing safety. The results from the pilot study will be leveraged to inform our larger randomized clinical trial designed to study the effect of zinc supplementation in nursing home elderly with low serum zinc levels on respiratory infections, antibiotic use, and duration of sick days with pneumonia. In tandem with dose optimization, we will evaluate the correlation between serum zinc and pan-T cell zinc levels, given that T cells and their zinc levels are important in the response and resolution of respiratory infections but whose correlation has only been extrapolated and not demonstrated.
C. Epidemiological studies suggest that increased fruit and vegetable (FV) intake is associated with a reduced risk of cognitive dysfunction. However, causal relationship between FV intake and cognition has not been established. As part of Objective 2, we investigated the causal effect of long-term FV supplementation in the context of a low-fat or Western-style high-fat diet in mice. Using a 2 × 2 factorial prospective design, male C57BL/6J (5-wk) were randomly assigned to one of four groups (20/group): low-fat control (LF-C, 10% kcal fat), high-fat control (HF-C, 45% kcal fat), and each with 15% of a unique mixture of FV (patent pending) (w/w) (LF-FV and HF-FV). Novel object recognition test (NOR), a cognitive test for measuring exploration, memory, and object recognition, was performed to evaluate mouse cognitive function at 18 months. Compared to the LF-C group, mice fed the HF diet for 18 months performed significantly lower in the NOR test, indicating cognitive impairment in the HF-C group. FV supplementation significantly mitigated the HF diet-induced cognitive impairment. No significant difference was observed between the LF-C mice and the LF-FV mice. This study provides evidence for a causal role of high intake of FV in preventing Western-style high-fat diet-induced cognition
impairment in mice. The mechanisms by which FV improves cognitive function is currently under investigation. In the same study, we noted that those mice fed a western-style high-fat diet had significantly higher tumor incidence and mortality compared to those fed the low-fat diet. These beneficial effects of FV are at least in part due to reduced inflammation and reduced blood lipids including cholesterol levels.
Accomplishments
Review Publications
Lewis, E., Ortega, E.F., Dao, M., Barger, K., Mason, J.B., Leong, J.M., Osburne, M.S., Magoun, L., Nepveux, F.J., Chishti, A.H., Schwake, C., Quyhn, A., Gilhooly, C.H., Petty, G., Guo, W., Matuszek, G.H., Pereira, D., Reddy, M., Wang, J., Wu, D., Meydani, S.N., Combs, G.F. 2023. Safe and effective delivery of supplemental iron to healthy adults: A two-phase, randomized, double-blind trial - the Safe Iron Study. Frontiers in Nutrition. https://doi.org/10.3389/fnut.2023.1230061.
Guo, W., Ortega, E., Wu, D., Li, L., Bronson, R.T., Boehm, S., Meydani, S.N. 2023. Life-long consumption of high level of fruits and vegetables reduces tumor incidence and extends median lifespan in mice. Frontiers in Nutrition. https://doi.org/10.3389/fnut.2023.1286792.
Ortega, E.F., Wu, D., Guo, W., Meydani, S., Panda, A. 2024. Study protocol for a zinc intervention in the elderly for prevention of pneumonia (ZIPP), a randomized, placebo-controlled, double-blind clinical pilot trial. Frontiers in Nutrition. https://doi.org/10.3389/fnut.2024.1356594.