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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

2019 Annual Report


Objectives
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.


Approach
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: This is the final report for the project 8050-51000-090-00D. During aging, the body’s immune function declines and becomes dysregulated. As such, aging increases the risk for developing lung infections like Streptococcus pneumoniae, one of the most common types of pneumonia in the elderly. We investigated whether vitamin E, an immune-modulating nutrient, can improve the age-associated decline in resistance to pneumococcal infection. Our results showed that old mice were more susceptible to pneumococcal infection than young mice, and that feeding extra vitamin E to aged mice reversed their vulnerability to disease caused by this bacterium. In determining the working mechanism, we further found that this protective effect of vitamin E was associated with decreased inflammatory infiltration of neutrophils (a type of white blood cell that can produce damaging inflammatory materials) into the lungs. These results have significant implications for the health and quality of life for older adults through reducing the risk of lung infections, one of the major causes of morbidity and mortality in elderly. Zinc is essential for immune cell function, and zinc supplementation has the potential to increase serum zinc concentrations and improve impaired immune function in the elderly. We conducted a study to determine the effect of supplementation with 30 mg zinc/day for 3 months on serum zinc concentrations and immune function in zinc-deficient elderly residing in nursing homes. We found that zinc supplementation increased serum zinc levels, increased the number of peripheral T cells, and enhanced T-cell proliferation. These results indicate that older subjects with low serum zinc levels should consider increasing their zinc intake to promote their health. Animal studies have shown that calorie restriction (CR) inhibits inflammation and slows aging but may on the other hand impair immunity against certain pathogens. Whether this is true in humans is currently unknown. In a collaborative multi-center, randomized clinical trial, we determined the effect of two years of CR on inflammation and cell-mediated immunity in healthy non-obese adults. We found that CR induced a 10% weight loss and reduction in circulating inflammatory markers, including total white blood cells and lymphocytes, and several soluble substances known to be involved in chronic inflammation. CR had no effect on the two key indices of immune function closely relevant to the body’s defense against harmful micro-organisms: delayed-type hypersensitivity skin response and antibody titer levels in response to vaccines, nor did it increase the risk of infection. These results represent the first evidence supporting that long-term moderate CR without malnutrition in humans can suppress inflammation without compromising the vigor of immunity. Given the established role of inflammation in the development of multiple chronic diseases, CR may represent a promising strategy for improving health and alleviating age-related diseases. Epidemiological studies indicate that whole grain (WG) consumption may be associated with lower inflammation, a key risk factor for developing chronic diseases (cardiovascular diseases, cancer, and diabetes), however, evidence from interventional studies is very limited. We thus conducted a study to compare WG with refined grain (RG) diets for their effect on several important markers of gut health and immune function. We found that the WG diet was well-tolerated by the participants and that compared to RG group, WG group had significant increases in stool weight and frequency, beneficial dietary fiber products, and some beneficial gut-residing bacteria known to have an anti-inflammatory effect. In addition, a modest beneficial change in immune function was observed. These results show, for the first time, that increasing consumption of whole grains without weight loss improves gut health and certain immune functions, and these observations have added new evidence supporting the current USDA dietary guidelines that recommend increased whole grain intake. Epidemiological studies have shown an inverse association between fruit and vegetable (F&V) consumption and incidence of cardiovascular disease. However, the evidence for causality and underlying mechanisms is lacking. In a close collaboration with the Vascular Biology Lab, we conducted a study using a high fat diet (HFD)-induced atherosclerosis animal model. We found that mice fed HFD had larger aortic atherosclerotic lesion and more severe fatty liver than those fed the control diet. Dietary supplementation with 15% F&V powder (composed of 24 F&V commonly consumed by Americans) prevented both aortic lesions and fatty liver by 80%. HFD induced higher pro-inflammatory cytokine TNFa, higher triglycerides and low-density lipoproteins (LDL), and lower high-density lipoproteins (HDL) in plasma, all of which were prevented by F&V supplementation. These results provide direct evidence for a causal role of high intake of F&V in preventing HFD-induced atherosclerosis and fatty liver, which may be mediated through improved blood lipids and reduced inflammation. The prevalence of obesity and metabolic disorders is rapidly increasing around the world. Fat accumulation in the liver can result in non-alcoholic fatty liver disease (NAFLD), a leading cause of liver cirrhosis and cancer. Increasing evidence points to the importance of gut microbiota in health and disease of the host. We conducted a study using 15% F&V supplementation as mentioned above in an animal model of HFD-induced obesity. We found that F&V reduced weight gain and fat mass, prevented adipose tissue inflammation, fatty liver, and obesity-induced immune impairment. We further showed that F&V decreased blood and tissue levels of ceramides, a family of sphingolipids linked to inflammation and insulin resistance. We also found that F&V increased fecal abundance and diversity of gut microbiota. Further data analysis showed several significant correlations among F&V-induced changes in metabolic parameters, inflammation markers, gut microbiota diversity, and ceramides. Together our results suggest a causal role of F&V intake in preventing obesity and its associated immune and metabolic disorders. Altered gut microbiota pattern and ceramide metabolism may play an important role in mediating these effects of F&V. 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 being conducted in two phases and is ongoing. VASCULAR BIOLOGY LAB: This is the final report for project 8050-51000-090-00D. Scientist retired and ended employment with Tufts University and lab closed 10/1/2018. Researchers in Boston, Massachusetts addressed Objective 1 and were the first to investigate the consumption of common edible mushrooms, specifically Portobello and shiitake, on heart health in an appropriate animal model of atherosclerosis. Researchers 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 indicated that a diet high in natural, whole foods may have a direct impact on diet-induced heart disease. By addressing Objective 2, researchers discovered that the risk of cardiovascular disease can be reduced by consuming oats. Inflammation of the blood vessels and high levels of cholesterol can contribute to the development of cardiovascular diseases, i.e. conditions that impact the heart and blood vessel system. They demonstrated that eating oats containing high levels of avenanthramides, a substance found naturally in all oats, reduces inflammation in blood vessels. The researchers specifically learned that avenanthramides are most beneficial for lowering inflammation and cholesterol when the oats have a high level of these avenanthramides. Since oats are an important U.S. agricultural product, these scientific results can be used to guide oat breeding in order to produce a crop with high levels of avenanthramides, thereby enhancing the health benefits of this food. Researchers in the Vascular Biology Lab made strides in the study of curcumin. Curcumin is a naturally occurring plant-based chemical derived from the root of the spice turmeric, which is traditionally used in the prevention and treatment of many diseases in Asian countries. Despite its low bioavailability, it lowers the levels of lipids in plasma and reduces obesity, which is known to be a key contributor to the development of several diseases. Researchers in the lab analyzed the molecular mechanisms by which curcumin may influence the plasma and tissue lipid levels in mice. They examined the accumulation and metabolism of fat in different cells by investigating the relationship of a transporter molecule called CD36 to another protein called cCAMP (cyclic adenosine monophosphate protein). Understanding the biological action of curcumin and its ability to alter these energy and transporter molecules would help us develop a method to eliminate excess body fat more efficiently in overweight and obese individuals.


Accomplishments
1. NUTRITIONAL IMMUNOLOGY LAB: Fecal biomarkers for measuring intestinal inflammation and permeability. Assessing intestinal biomarkers for intestinal inflammation and permeability can be time-consuming and labor-intensive, with limited quantitative capabilities and variable recoveries. Therefore, a single extraction procedure with good efficacy and reproducibility would be helpful in their application in both research and clinical settings. To meet this need, ARS-funded researchers in Boston, Massachusetts, used a single extraction procedure to process fecal samples from adults in the U.S. quantified the four different markers to validate the application of this modified method. Results showed that recovery was greater than 80 percent for three biomarkers. This study shows that the single extraction procedure is sensitive, time-saving, and cost-effective, and can be used.


Review Publications
Wu, D., Meydani, S.N. 2019. Vitamin E, immune function, and protection against infection. In: Weber P, Birringer M, Blumberg JB, Eggersdorfer M., Frank J., editors. Vitamin E in Human Health. Springer Nature, New York, NY. p. 371-384. https://doi.org/10.1007/978-3-030-05315-4_26.
Lewis, E.D., Meydani, S.N., Wu, D. 2018. Regulatory role of vitamin E in the immune system and inflammation. International Union of Biochemistry and Molecular Biology Life. 71(4). https://doi.org/10.1002/iub.1976.