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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Research Project #436103

Research Project: Nutrition, Immune and Inflammatory Responses, and Related Diseases

Location: Jean Mayer Human Nutrition Research Center On Aging

2022 Annual Report

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.

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
Observational studies suggest the potential for higher consumption of fruits and vegetables (F&V) to prevent obesity, improve metabolic and immune health, and expand health- and lifespan. However, causal relation has not been demonstrated, and the mechanisms need to be determined. We conducted studies to address these gaps. Pre-clinical animal studies, using both longitudinal (LG) and cross-sectional (CS) design, were conducted to determine the effect of F&V on health and median lifespan, gut microbiota, oxidative stress, ceramides, inflammatory cytokines and T cell profile and function, using lean and obese mice. First, we conducted two 6-month studies using wild-type and atherosclerosis-prone LDL receptor knock out (LDLR-KO) mice and showed that F&V supplementation prevents high-fat diet/obesity-induced metabolic disorders including non-alcoholic fatty liver disease and atherosclerosis. We then conducted a longitudinal study to determine the causal effect of F&V on health- and lifespan. Two hundred forty male mice (60 mice/group) were randomly assigned to four diets: low fat (LF), and high fat (HF) without and with 15% F&V, the optimal dose determined previously. Mice were weighed weekly. Body composition was assessed using MRI at 6 and 16 months. Blood was collected at 6 months and at termination (21 months) to determine ceramide, cytokine levels and T cell profile. Feces were collected at 0-, 6-, 16- and 21-months for microbiota analysis. Cognitive function was assessed at 18 months. Mice were terminated when the first diet group reached 50% mortality, at which time all groups were euthanized, and tissues were collected for biochemical and pathological assessments. We showed that mice fed the high fat diet with F&V had significantly lower weight gain and fat mass. Mice fed the HF diet had significantly lower percentage of total T lymphocytes and helper T cells (also known as CD4-positive cells) compared to those fed the LF diet. F&V supplementation restored total T lymphocytes and the helper T cell population that was impaired by the HF diet. To test of cognition, we collaborated with ARS scientist on the neuroscience team and showed that mice fed the HF diet had impaired cognitive function compared to those fed the LF diet, which was prevented by F&V supplementation. We have completed analysis of cytokines and ceramides as well as partial analysis of gut microbiota. Currently, we are conducting statistical analysis of the ceramide and cytokine data and awaiting completion of gut microbiota analysis. Ex-vivo analysis of T cell function is in process. The results from this analysis will provide information regarding the mechanisms of F&V-induced effect as well as the role of ceramide, inflammatory cytokines and gut microbiome on the aging process. The forms of iron (mainly ferrous sulfate) currently available for humans have adverse effects that limit their use in addressing prevalent iron deficiency. We have conducted a clinical trial to test the safety of 3 different forms of iron (Fe). The study was conducted in two phases each comprised of a randomized, double-blinded, placebo-controlled trial conducted with iron-replete adults. These trials compared subject responses to ferrous sulfate and two novel forms of iron that have been shown to be bioavailable: nanoparticulate iron hydroxide adipate tartrate (IHAT), and an organic fungal iron metabolite (Aspiron™ Natural Koji Iron, ASP). The Study tested the hypotheses that of IHAT and ASP are each safe as indicated by three parameters: susceptibility to malaria infection (assessed ex vivo), bacterial proliferation (assessed ex vivo), and gut inflammation. In Study Phase I, 160 subjects were randomized to six treatments comprised of IHAT, ASP and ferrous sulphate (FeSO4·7H2O) each administrated at the level of 60 mg Fe/day, with FeSO4·7H2O also administered with a multiple micronutrient powder or as a single weekly dose of 420 mg Fe. In Study Phase II, 86 subjects were randomized to IHAT, ASP or ferrous sulphate administered at a therapeutic dose level of 120 mg Fe/day. All study related activities have been completed. Data analysis is for the most part completed. We are currently in the process of finishing data analysis, summarizing the results and preparation of manuscripts. Previously we showed that 30% of nursing home residents in US have low serum zinc level and that those with low serum zinc level had twice as many pneumonias, longer duration of pneumonia and higher antibiotic use during the one-year period of the study. These results strongly suggest that zinc plays a key role in prevention of pneumonia, however a prospective clinical trial is needed before zinc can be recommended for prevention of pneumonia in elderly. Subsequently, we conducted a study to determine if supplementation with 30 mg/day of zinc gluconate will reverse low serum zinc levels in elderly as well as improve their T cell function. We found that while, on average, supplementation with 30 mg/day of zinc improved serum zin levels, only 60% of elderly with low serum zinc levels exhibited change to adequate serum zinc levels, suggesting that either higher than 30 mg/day or a longer period of supplementation will be needed to achieve adequate serum zinc level in all subjects. We also observed a significant improvement in T cell-mediated function and a significant correlation between serum zinc level and T cell function. Currently, we are conducting a dose response study in elderly nursing home residents with low serum zinc level to determine the efficacious and safe dose of zinc to be used in a larger clinical trial, the primary outcome of which will be incidence of pneumonia. If as we have hypothesized, zinc supplementation reduces susceptibility of elderly to pneumonia, the findings of this study would have a significant public health impact and could influence clinical practice for prevention of pneumonia. So far 250 individuals have been screened. Prescreening blood draws started in May 2022. Out of 24 individuals who gave consent for blood draws so far, 19 had low zinc levels. This incidence is significantly higher than we predicted which highlights the public health importance of this project and makes us optimistic that we will be able to recruit the targeted number of 105 individuals. A total of 13 individuals have been enrolled and randomly assigned to placebo (1/2 RDA of essential micronutrients), 30 mg zinc + 1/2 RDA of essential micronutrients, or 60 mg zinc + 1/2 RDA of essential micronutrients. So far, no adverse events have been recorded. Screening and enrollment are ongoing. Measurement of intracellular zinc and immunoassays have been optimized and will be performed on all individuals at baseline, 4, 8 and 12 months. The results of this study will determine the dose of zinc to be used in the larger clinical trial. Further it will determine correlation between serum zinc and intracellular zinc level as well as T cell function.

1. Fruits and vegetables improve lifespan and decrease tumors. The positive association of life-long consumption of fruits and vegetables (F&V) on cancer and mortality has been identified in epidemiological and observational studies, but not in experimental studies. ARS-funded researchers in Boston, Massachusetts, have provided the first causal evidence that consumption of the equivalent of eight daily servings of a wide variety of F&V extends lifespan and decrease tumors in mice fed a Western-style high-fat diet. In the experiments, the mice fed the high-fat diet had fifty-percent higher mortality compared to twenty-three percent for those fed the High-fat diet with F&V and eighteen percent for those fed the low-fat diet. Furthermore, tumor incidence in mice fed the high-fat diet seventy-three percent was significantly higher than that in mice fed the low-fat diet at thirty-percent. These results demonstrate that F&V extends health- and lifespan in mice and provide a foundation for further investigation into the benefits of fruit and vegetable supplementation on aging and age-related disease.

Review Publications
Lee, Y., Kim, Y., Lee, M., Wu, D., Pae, M. 2021. Time-restricted feeding restores obesity-induced alteration in adipose tissue immune cell phenotype. Nutrients. 13(11):3780.
Guo, W., Kim, S.H., Wu, D., Li, L., Ortega, E.F., Thomas, M., Meydani, S.N., Meydani, M. 2021. Dietary fruit and vegetable supplementation suppresses diet-induced atherosclerosis in LDL receptor knockout mice. Journal of Nutrition. 151(4):902-910.
Guo, W., Wu, D., Dao, M.C., Li, L., Lewis, E., Ortega, E.F., Eorn, H., Thomas, M., Nikolova-Karakashian, M., Meydani, M., Meydani, S.N. 2020. A novel combination of fruits and vegetables prevents diet-induced hepatic steatosis and metabolic dysfunction in mice. Journal of Nutrition. 150(11):2950-2960.
Joma, B.H., Siwapornchai, N., Vanguri, V.K., Shrestha, A., Roggensack, S.E., Davidson, B.A., Tai, A.K., Hakansson, A.P., Meydani, S.N., Leong, J.M., Bou Ghanem, E.N. 2021. A murine model for the transition of Streptococcus pneumoniae from asymptomatic colonizer to systemic pathogen. American Society for Microbiology.
Joma, B.H., Siwapornchai, N., Vanguri, V.K., Shrestha, A., Roggensack, S.E., Davidson, B.A., Tai, A.K., Hakansson, A.P., Meydani, S.N., Leong, J.M., Bou Ghanem, E.N. 2021. A murine model for enhancement of Streptococcus pneumoniae pathogenicity upon viral infection and advanced age. Infection and Immunity. 89(8):e00471-20.
Nam Lee, M., Lee, Y., Wu, D., Pae, M. 2021. Luteolin inhibits NLRP3 inflammasome activation via blocking ASC oligomerization. Journal of Nutritional Biochemistry. 92:108614.
Nimitphong, H., Guo, W., Holick, M.F., Fried, S.K., Lee, M. 2021. Vitamin D inhibits adipokine production and inflammatory signaling through the vitamin D receptor in human adipocytes. Obesity. 29(3):562-568.