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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

2020 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
Previously we showed that supplementing a high fat diet (HFD) with 15% fruits and vegetables (F&V) (composed of 24 F&V commonly consumed by Americans) prevented HFD-induced non-alcoholic fatty liver disease (NAFLD). The major pathogenic mechanisms for NAFLD development include elevated oxidative stress and inflammation. F&V contain a variety of antioxidant nutrients and non-nutrient phytochemicals. Therefore, we hypothesized that the observed preventive effect of F&V on NAFLD may be due to the antioxidant activity of the antioxidant components in F&V. To test this hypothesis, we analyzed samples collected from the previous study for lipid peroxidation assessment, and conducted correlation analysis for the relationship among NAFLD, and the NAFLD risk factors including pro-inflammatory molecule TNF-a, lipid peroxidation biomarker malondialdehyde (MDA), and sphingolipid molecule ceramide as well as an enzyme for its generation. We found that HFD-induced fatty liver, and higher levels of the above-mentioned risk factors in blood and liver, and all these HFD-induced changes were prevented by F&V supplementation. We further found that liver MDA levels were positively correlated with severity of fatty liver, levels of TNF-a and ceramide, and activity of the enzyme responsible for ceramide release, neutral sphingomylinase (nSMase). Together, these results suggest that prevention of NAFLD by F&V might be mediated through reduction in oxidative stress leading to suppressed production of pro-inflammatory molecule TNF-a (risk factor for NAFLD), as well as decrease in nSMase, and thus ceramide levels. Both obesity and the number of older adults continue to increase globally, which is closely associated with increased metabolic disorders, chronic diseases, and the incidence of infection leading to reduced health- and life-span and steady increase in health care costs. Observational studies suggest potential for higher consumption of fruits and vegetables (F&V) to prevent obesity, improve metabolic and immune health, and expand health- and life-span. However, causal relation has not been demonstrated, and the mechanisms needs to be determined. We are conducting studies to address both these gaps. Pre-clinical animal studies, using both longitudinal (LG) and cross-sectional (CS) design, are conducted to allow us to determine the effect of F&V on health and median life span, gut microbiota, oxidative stress, ceramides, inflammatory cytokines and T cell profile, using the same groups of lean and obese mice. Further, we will be able to compare F&V effect, between groups at different stages of life, on various metabolic parameters and pathologies, immune function, inflammation, oxidative stress, and infection. Both LG and CS studies have four diet groups (low fat, high fat, without and with F&V). The LG study (240 mice; 60 mice/group) was started in the beginning of last September, and the body weights and food intakes have been recorded at planned intervals without interruption. At the first time point (6-month), we were just able to collect fecal samples and conducted body composition measurement for all 240 mice right before the lockdown and suspension of all research activity due to COVID-19, but were unable to collect blood samples. Based on the weight gain and body composition results thus far, the model works well, and F&V supplementation is effective, i.e., mice fed the high fat diet had more weight gain and fat mass, which are reduced by F&V supplementation. F&V supplementation does not impact weight gain in mice fed the LF diet. In late January of this year, we started the 6-month cross-sectional study (60 mice, 15 mice/group) and these mice are projected to be terminated in the middle of July for sample collection and analysis. The forms of iron (mainly ferrous sulfate) currently available have serious adverse effects that limit their use in addressing prevalent iron deficiency. We are conducting a clinical trial to test whether two novel sources of iron, a nanoparticulate form (IHAT) and a fungal form (Aspiron), would be better choices in terms of their effects on host susceptibility to malaria and bacterial proliferation, iron utilization and other adverse effects (irritation of the gut, promotion of local/systemic inflammation, promotion of oxidative stress, and perturbation of the gut microbiome). The study is conducted in two phases. All the participant visits and sample collection for Phase I have been completed. A total of 161 participants were enrolled, 6 dropped, and 150 completed the Phase I study. Completed analyses of the outcomes include blood cell counts, fecal immunochemical tests (FIT), blood markers for iron status, the bacterial proliferation assay, and malaria growth assay. Majority of fecal samples have been analyzed for gut inflammation markers calprotectin (CP), alpha-1-antitrypsin (AAT), myeloperoxidase (MPO), and neopterin (NEO). Analysis of blood ex-vivo cytokine production tumor necrosis factor alpha (TNF-a), interleukin-6 (IL-6), and interleukin-2 (IL-2) has started for Phase I. Phase II study started in August 2019. At the time of the COVID-19 lockdown, we had completed 43 participant visits and sample collection, 7 participants were scheduled for second visits and 10 were enrolled into the study.

1. Obesity makes young women's health respond like the elderly. Both obesity and aging are linked with reduced immunity and increased inflammation. ARS-funded researchers in Boston, Massachusetts, compared the response of circulating immune cells between young and older women with obesity. They found that obesity hastens the aging of the immune and inflammatory responses, making obese women more vulnerable to infection, cancer, and other inflammatory diseases.

Review Publications
Dao, M.C., Saltzman, E., Page, M., Reece, J., Mojtahed, T., Wu, D., Meydani, S.N. 2020. Lack of differences in inflammation and T cell-mediated function between young and older women with obesity. Nutrients. 12(1):237.
Meydani, S.N., Lewis, E.D., Wu, D. 2018. Perspective: should vitamin E recommendations for older adults be increased? Advances in Nutrition. 9(5):533-543.
Wu, D., Lewis, E.D., Pae, M., Meydani, S.N. 2019. Nutritional modulation of immune function: analysis of evidence, mechanisms, and clinical relevance. Frontiers in Immunology. 9:3160.
Guida, J.L., Agurs-Collins, T., Ahles, T.A., Campisi, J., Dale, W., Demark-Wahnefrie, W., Dietrich, J., Fuldner, R., Gallicchio, L., Green, P.A., Hurria, A., Janelsins, M.C., Jhappan, C., Kirkland, J.L., Kohanski, R., Longo, V., Meydani, S.N., Mohile, S., Niedernhofer, L.J., Nelson, C., Perna, F., Schadler, K.L., Scott, J.M., Schrack, J.A., Russell, T.P., Van Deursen, J., Ness, K.K. 2020. Strategies to prevent or remediate cancer- and treatment-related aging. Journal of the National Cancer Institute.
Eggersdorfer, M., Akobundu, U., Bailey, R.L., Shlisky Baxter, J., Beaudreault, A.R., Bergeron, G., Blancato, R.B., Blumberg, J.B., Bourassa, M.W., Gomes, F., Jensen, G., Johnson, M., Mackay, D., Marshall, K., Meydani, S.N., Tucker, K.L. 2018. Hidden hunger: solutions for America's aging populations. Nutrients. 10(9):1210.
Lewis, E.D., Wu, D., Mason, J.B., Chishti, A.H., Leong, J.M., Barger, K., Meydani, S.N., Combs, G.F. 2019. Safe and effective delivery of supplemental iron to healthy older adults: the double-blind, randomized, placebo-controlled trial protocol of the Safe Iron Study. Gates Open Research. 3:1510.
Zhang, J., Nle, S., Zu, Y., Abbasi, M., Cao, J., Li, C., Wu, D., Labib, S., Brackee, G., Shen, C., Wang, S. 2019. Anti-atherogenic effects of CD36-targeted epigallocatechin gallate-loaded nanoparticles. Journal of Controlled Release. 303:263-273.