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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Research Project #426379

Research Project: Immunity, Inflammation, and Nutrition in Aging

Location: Jean Mayer Human Nutrition Research Center On Aging

2018 Annual Report

LAB NAME: Nutritional Immunology 1: Determine the impact and underlying mechanisms of obesity during pregnancy on newborn's life-long immune and inflammatory responses and resistance to infectious diseases in appropriate animal models. 1A. To investigate the impact of maternal obesity on immune function and influenza infection in young offspring. 1B. To determine the role of inflammatory, oxidative stress, and selected epigenetic markers that are critical for immune response to influenza and the higher susceptibility of obese mothers’ offspring to influenza infection. 1C. To determine the impact of maternal obesity on immune function and resistance to infection through the life cycle. 2: Determine the effect and mechanisms of food components such as fruits and vegetables or whole grains influence on, and their interaction with, age on immune and inflammatory responses and related diseases in both animal models and human studies. 2A: To determine the impact of increased consumption of F&V on prevention of key age-related biologic dysfunctions and pathologies in a suitable animal model. 2B: To determine the effect of consumption of an isocaloric diet rich in whole grains (WG)[compared to refined grains (RG)] on gut microbiota, and immune and inflammatory responses. 3: Determine the effect of novel forms of iron on systemic and gut immune function, inflammation, oxidative stress. LAB NAME: Vascular Biology 1: Determine the effectiveness and underlying mechanisms of fruits/vegetables and Mediterranean style diets or their specific bioactive components in the prevention of atherosclerosis and survival using animal models of humans. 1A: Determine the effectiveness and underlying mechanisms of increased consumption F&V diets on prevention of atherosclerosis and survival using appropriate animal model of human atherosclerosis. 1B: Determine the effectiveness of natural bioactive polyphenols of foods and spices and their underlying mechanisms on prevention of atherosclerosis using appropriate animal models of human atherosclerosis. 2: Determine the efficacy of fruits/vegetables, avenanthramides from oats, and selected other bioactive compounds on alteration of microbiome and anti-microbial peptides, suppression of chronic inflammation of the GI tract, prevention of colon cancer and atherosclerosis in appropriate animal models. Under this objective, we will pursue the following sub-objectives: 2A: Determine the efficacy of bioactive phosphorylated tocopherols ('Tp) versus tocopherols on age-dependent decline of angiogenesis and suppression of atherosclerosis in vivo and ex-vivo. 2B: To determine the molecular signaling mechanisms by which 'TP induces angiogenesis. 3: Determine the effect of eight weeks consumption of an isocaloric diet enriched with whole grains (compared to refined grains) on gut microbiota, inflammatory and other risk predictors of atherosclerosis.

NUTRITIONAL IMMUNOLOGY: Aging is associated with dysregulation of immune and inflammatory responses, which contribute to several age-related diseases. Nutritional status including that during early life has been linked to health status of older adults, & nutritional interventions during different life stages including those during pregnancy are reported to have long-lasting effects on the health status of newborns. Long-term goal is to determine the underlying mechanisms of age-related immune & inflammatory dysregulation in order to develop nutritional interventions, which will prevent/reduce these alterations. [1] will determine the impact & underlying mechanisms of obesity during pregnancy on newborn's life-long immune & inflammatory responses & resistance to infectious diseases. To achieve this, we will use a diet-induced obesity mouse model and determine: 1) effect of maternal obesity on immune function and influenza infection in young offspring, 2) role of inflammatory, oxidative stress, and selected epigenetic markers in altered immune function and susceptibility to infection in offspring born to obese mothers, and 3) impact of maternal obesity on immune function and resistance to infection through the life cycle. [2] will determine the effect and mechanisms of food components such as fruits and vegetables or whole grains influence on, and their interaction with, age on immune and inflammatory responses and related diseases in both animal models and human studies. [2A], we will use a mouse model to determine whether the dietary supplementation with a variety of fruits and vegetables would impact health- and life-span through modulating oxidative stress, inflammation and the regulatory lipid, ceramide. [2B], we will conduct a dietary intervention trial in healthy middle-aged human participants to determine the effect of consumption of an isocaloric diet rich in whole grains compared to refined grains on gut microbiota, and immune and inflammatory responses. These studies will help develop effective strategies to improve health- and life-span of the aged through optimization of immune and inflammatory responses. VASCULAR BIOLOGY: Determine survival rates, prevention of atherosclerosis, and underlying mechanism(s) in LDLr-/- young to old mice using freeze-dried fruits, vegetables and cereal grains in a high fat diet. Further, we will use C57/BL and LDLr-/- mice to determine the causal relationship & underlying mechanism(s) of specific bioactive food components (such as curcumin, resveratrol, avenanthramides, and their combinations) on inhibition of dyslipidemia, fatty liver, inflammation, metabolic disorders, & atherosclerosis resulting from consuming a diet high in fat and/or sweeteners like sucrose & high fructose corn syrup. We plan to establish the causal relationship of increased consumption of whole grains versus refined grains and their capacity to improve oxidative & antioxidant status as well as surrogate markers of cardiovascular disease. We will investigate potential molecular mechanisms by which alpha-Tocopheryl phosphate (alpha-TP), a natural derivative of alpha-T, induces angiogenesis in vitro & in an in vivo animal model.

Progress Report
NUTRITIONAL IMMUNOLOGY LAB: We have previously shown that dietary supplementation with the alpha-tocopherol form of vitamin E (a-Toc) decreases pulmonary inflammation and reverses age-associated decline in resistance to pneumococcal pneumonia in mice. To link these findings to humans, we used neutrophils isolated from young (22-35 y) or older (65-69 y) individuals to test the effect of a-Toc on the ability of these cells to migrate across epithelial cell monolayers in response to S. pneumoniae and to kill complement-opsonized pneumococci. We found that basal levels of pneumococcal-induced trans-epithelial migration by neutrophils from young or elderly donors were indistinguishable, suggesting that the age-associated exacerbation of pulmonary inflammation is not due to intrinsic properties of neutrophils of elderly individuals but may reflect the inflammatory milieu of the aged lung. Unlike previous studies in mice, we found that neutrophils of elderly donors were more efficient at killing complement-opsonized bacteria than younger counterparts. We also found the heightened antimicrobial activity in neutrophils from older donors correlated with increased activity of neutrophil elastase, a serine protease required to kill pneumococci. Notably, a-Toc increased PMN (Polymorphonuclear leukocytes) elastase activity from young donors and boosted their ability to kill complement-opsonized pneumococci. These findings indicate that a-Toc can be used as a potential nutritional intervention to combat pneumococcal infection. Although commensal bacteria are crucial in maintaining immune homeostasis of the intestine, little is known about their role in shaping the immune inductive function in a non-intestinal mucosal surface such as the lung. We conducted a study to look at the pulmonary microbiome of healthy older individuals through analysis of high-throughput 16SrDNA sequence data from broncho-alveolar lavage. Preliminary data suggest differences between the quantity and types of bacteria sampled from broncho-alveolar lavage of older and young individuals. These studies are ongoing. We conducted a study in mice to address the effect of blueberries on systemic immune functions. Mice were fed one of three diets: low-fat diet (LFD), high-fat diet (HFD), and HFD plus 4% (w/w) blueberries (HFD+B) for 8 or 12 wk. Ex vivo T-cell mitogens (concanavalin A; phytohaemagglutinin), T-cell antibody (anti-CD3; anti-CD3/CD28)-stimulated T-cell proliferation and cytokine production were assessed. After 8 wk, both HFD groups weighed on average 4g more than the LFD group; after 12 wk, HFD+B-fed mice weighed on average 6g more and had 41% more adipose tissue than HFD-fed mice (P<0·05). At 12 wk, T-cell proliferation was lower in in HFD compared to LFD, which was partially (10-50%) prevented by addition of blueberries. In addition, spleen cells from HFD mice, but not from HFD+B mice, produced 51% less IL-4, 57% less interferon-gamma, 24-30% less IL-6, and 27-33% less TNF-a (TNFalpha) compared with LFD mice, indicating impaired innate immune response. These results provide insights on how the protective effects of blueberries can buttress T-cell and systemic immune function against HFD/obesity-associated insults. Epidemiologic studies suggest that consumption of fruits and vegetables (F&V) is associated with reduced risk of age-related diseases and may contribute to longevity. To determine the causal relationship and long-term effects we formulated a unique F&V mixture containing 24 commonly consumed F&V and administered it to mice in a high-fat diet-induced obesity model for 20 wk. We found that compared to the control, feeding 15% F&V (equivalent to 8-9 servings of F&V) reduced weight gain and fat mass, prevented adipose tissue inflammation, fatty liver, and immune impairment, and increased fecal energy secretion and abundance and diversity of gut microbiota. Lipidomic analysis showed that these biological and microbial changes were linked to sphingolipid metabolism through a unique pathway. These results suggest a causal role of F&V intake in preventing obesity and its associated immune and metabolic disorders and have significant implications for developing cost-effective nutritional strategies. 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. The development of the assay to assess Plasmodium falciparum invasion and growth in human red blood cells has been ongoing. The analysis of experimental samples will soon commence. Iron status and several inflammatory parameters have been conducted on 40 subjects to ensure methods were within range and optimized for this study. A series of validation and optimization tests were also conducted including those for analysis of calprotectin, myeloperoxidase, neopterin, a1-antitrypsin in fecal samples, and inflammatory markers in serum. There has been ongoing development of LC-MS/MS methods to measure several parameters proposed (tryptophan, kynurenine, short chain fatty acids). VASCULAR BIOLOGY LAB: Epidemiologic studies suggest that consumption of fruits and vegetables is associated with reduced risk of age-related diseases such as obesity, diabetes, cardiovascular disease, stroke, and cancer and may contribute to longevity. However, the benefit of fruits and vegetables for prevention of these conditions has been documented most often as an “association in observational studies,” while there is little evidence to prove a causal relationship. Thus, we conducted a study to address how fruit and vegetable consumption will affect atherosclerosis, a primary abnormal change associated with cardiovascular disease. We selected 12 fruits and 12 vegetables commonly consumed in the US and prepared a freeze dried powder from this combination, which we incorporated (at 15%) into a high fat diet fed to LDLr-/-mice for 19 weeks. The feeding and tissue collection were already completed. The results obtained so far show that mice consuming the high fat diet with fruits and vegetables had similar food intake but less weight gain and less body fat compared to those consuming the high fat diet alone. The samples collected will be analyzed for aorta lesion, blood lipid profile, serum inflammatory markers and biochemistry, and liver enzymes involved in lipid metabolism. The results for these measurements will be completed and reported later. In collaboration with the Energy Metabolism Laboratory, we have been investigating the body fat-reducing effect of enzymatically-modified isoquercetrin, a natural bioactive polyphenol with potential health benefits and the capacity to prevent development of various diseases including those of the cardiovascular system and central nervous system. A total of 50 overweight and obese subjects were randomly assigned into two groups: 25 subjects to a placebo control group and 25 subjects to the treatment group (360 mg of enzymatically-modified isoquercetrin /d for 3 months). At the time of our last progress report, we had 25 subjects enrolled. Over the past year, a total of 50 subjects were enrolled, 47 have completed the study, and the remaining 3 are on the course for finishing at the end of July. Several parameters, including body composition by dual-energy x-ray absorptiometry, resting metabolic rate and skin fold, are being measured for efficacy while other parameters, such as heart, kidney, and liver function, are being measured for safety evaluation. Among the participants thus far, only three subjects reported an adverse effect and were dropped from the study. After all subjects have completed the study, measurements and statistical analysis will take place and a final report will be delivered to the sponsor. We have been studying the effect of two commonly consumed edible mushrooms, portobello mushroom and shiitake mushroom, on the prevention of atherosclerosis and associated inflammation in LdLr-/- mice, an animal model of human atherosclerosis. We found that adding 10% mushroom powder to the mice’s diets reduced their body fat and weight gain during 16 weeks of study. We also found that both shiitake mushroom and portobello mushroom effectively reduced body weight gain compared to mice fed a high fat diet. Quantitative en-face analysis of aortic lesions using Oil Red O staining and histology of the aortic tricuspid valve revealed that mice fed high fat shiitake mushroom and high fat portobello mushroom diets had significantly fewer aortic atherosclerotic lesions compared to those fed the high fat control diet. In this period, we performed additional analysis on the samples. Our additional analysis found that mushroom supplementation reduced inflammatory cytokine levels and VCAM-1 expression, an adhesion molecule involved in inflammation of the arteries. Plasma total lipid levels, including LDL-cholesterol, HDL-cholesterol, total cholesterol, and triglycerides, were also reduced by shiitake mushroom and portobello mushroom treatment. Our results indicate that commonly consumed mushrooms suppress dietary fat-induced atherosclerosis, an inflammatory disease of the arteries.

1. Eating citrus fruit may reduce incidences and severity of autoimmune diseases. Autoimmune diseases, in which the body’s immune system attacks its own cells, affect an estimated 20 percent of the U.S. population. Common medical treatments for these conditions, including conditions such as lupus, rheumatoid arthritis, psoriasis, and multiple sclerosis, have limited effectiveness and can cause significant side effects. ARS-funded researchers in Boston, Massachusetts conducted two studies using naringenin, a flavonoid substance found in high levels in citrus fruits, and found that it reduced the incidence, delayed onset, and reduced the symptoms in a mouse model of human multiple sclerosis known as Experimental Autoimmune Encephalomyelitis. These results suggest that increased consumption of citrus fruits, notably grapefruit and oranges that contain naringenin, may be beneficial in improving resistance to autoimmune diseases by lowering inflammation associated with autoimmune diseases.

2. Commonly consumed mushrooms improve heart health. Atherosclerosis, a disease that narrows blood vessels, can lead to heart disease, which is the primary cause of death in Western and developed societies. With the current obesity epidemic, diet is increasingly recognized as a primary approach to preventing heart and other serious, chronic diseases, and studies have shown that regular consumption of fruits and vegetables is associated with a lower risk of heart disease. To our knowledge, ARS-funded researchers in Boston, Massachusetts are the first to investigate the consumption of common edible mushrooms, specifically portobello and shiitake, on heart health in an appropriate animal model of atherosclerosis. We found that both shiitake and portobello mushrooms reduced diet-induced atherosclerosis by reducing weight gain, body fat, inflammation, narrowing of blood vessels and by lowering levels of fat in the bloodstream, suggesting that certain compounds found naturally in common mushrooms may be beneficial in reducing the risk of atherosclerosis. These results further indicate that a diet high in natural, whole foods may have a direct impact on diet-induced heart disease.

Review Publications
Miyazawa, T., Nakagawa, K., Kim, S.H., Thomas, M.J., Paul, L., Zingg, J., Dolnikowski, G.G., Roberts, S.B., Kimura, F., Miyazawa, T., Azzi, A., Meydani, M. 2018. Curcumin and piperine supplementation of obese mice under caloric restriction modulates body fat and interleukin-1beta. Nutrition and Metabolism. 15:12.
Thomas, M., Kim, S., Collins, F., Wise, M.L., Meydani, M. 2018. High levels of avenanthramides in oat-based diet further suppress high fat diet-induced atherosclerosis in Ldlr-/- mice. Journal of Nutrition. https:/
Wang, J., Qi, Y., Niu, X., Tang, H., Meydani, S.N., Wu, D. 2018. Dietary naringenin supplementation attenuates experimental autoimmune encephalomyelitis by modulating autoimmune inflammatory responses in mice. Journal of Nutritional Biochemistry. 54:130-139.
Meydani, M., Azzi, A. 2017. Dietary antioxidants and bioflavonoids in atherosclerosis and angiogenesis. In: Kussman, M., Stover, P.J., editors. Nutrigenomics and Proteomics in Health and Disease: Towards A Systems-Level Understanding of Gene-Diet Interactions. 2nd edition. Hoboken, NJ: John Wiley & Sons, Inc. p. 125-142.
Wu, D., Meydani, S. 2017. Vitamin E, immunity, and infection. In: Calder, P.C., Kulkarni, A.D., editors. Nutrition, Immunity and Infection. Boca Raton, FL: Taylor & Francis Group. p. 197-212.
Bermon, S., Castell, L.M., Calder, P.C., Bishop, N.C., Blomstrand, E., Mooren, F.C., Krugeer, K., Kavazis, A.N., Quindry, J.C., Senchina, D.S., Nieman, D., Gleeson, M., Pyne, D.B., Kitic, C.M., Close, G.L., Larson-Meyer, D., Marcos, A., Meydani, S.N., Wu, D., Walsh, N.P., Nagatomi, R. 2017. Consensus statement: immunonutrition and exercise. Exercise Immunology Review. 23:8-50.
Wu, D. 2016. Green tea EGCG, T-cell function, and T-cell-mediated autoimmune encephalomyelitis. Journal of Investigative Medicine. 4(8):1213-1219.
Shilsky, J., Bloom, D.E., Beaudreault, A.R., Tucker, K.L., Keller, H.H., Freund-Levi, Y., Fielding, R.A., Cheng, F.W., Jensen, G.L., Wu, D., Meydani, S.N. 2017. Nutritional considerations for healthy aging and reduction in age-related chronic disease. Advances in Nutrition. 8:17-26.
Zingg, J., Azzi, A., Meydani, M. 2014. Induction of VEGF expression by alpha-tocopherol and alpha-tocopheryl phosphate via PI3Kgamma/PKB and hTAP1/SEC14L2-mediated lipid exchange. Journal of Cellular Biochemistry. 116:398-407.
Zingg, J., Azzi, A., Meydani, M. 2017. Alpha-Tocopheryl phosphate induces VEGF expression via CD36/PI3Kgamma in THP-1 monocytes. Journal of Cellular Biochemistry. 118:1855-1867.
Chung, H., Wu, D., Smith, D.E., Meydani, S.N., Han, S. 2016. Lower hepatic iron storage associated with obesity in mice can be restored by decreasing body fat mass through feeding a low-fat diet. Nutrition Research. 36(9):955-963.
Bou Ghanem, E.N., Clark, S., Du, X., Wu, D., Camilli, A., Leong, J.M., Meydani, S.N. 2015. The alpha-tocopherol form of vitamin E reverses age-associated susceptibility to Streptococcus pneumoniae lung infection by modulating pulmonary neutrophil recruitment. Journal of Immunology. 194:1090-1099.
Lewis, E.D., Ren, Z., DeFuria, J., Obin, M.S., Meydani, S.N., Wu, D. 2018. Dietary supplementation with blueberry partially restores T cell-mediated function in high fat diet-induced obese mice. British Journal of Nutrition. 119(12):1393-1399.
Niu, X., Wu, C., Li, M., Zhao, Q., Meydani, S.N., Wang, J., Wu, D. 2018. Naringenin is an inhibitor of T cell effector functions. Journal of Nutritional Biochemistry. 58:71-79.
Pae, M., Baek, Y., Lee, S., Wu, D. 2018. Loss of ovarian function in association with a high-fat diet promotes insulin resistance and disturbs adipose tissue immune homeostasis. Journal of Nutritional Biochemistry. 57:93-102.
Jung, Y., Wu, D., Smith, D.E., Meydani, S.N., Han, S. 2018. Dysregulated 1,25-dihydroxyvitamin D levels in high fat diet-induced obesity can be restored by changing to a lower fat diet in mice. Nutrition Research. 53:51-60.