Research Project: Nutrition, Brain, and Aging

Location: Jean Mayer Human Nutrition Research Center On Aging

2018 Annual Report

Objectives
Objective 1: Characterize the effects of genetic, metabolic, and environmental influences on the aging brain and vasculature and the modifying impact of nutrition on neuronal function, cognition, and behavioral outcomes. Sub-objective 1A: Use human observational data to evaluate the relationships between nutrients/ bioactives, age-related cognitive decline, and neurodegenerative diseases, and characterize interactions between diet and genes, and environmental influences on these outcomes. Sub-objective 1B: Use human intervention studies as translational studies to determine the effects of intervention with specific nutrients or bioactives on cognitive and behavioral function. Sub-objective 1C: Use animal and cell models to develop mechanistic interpretations of the benefits of nutrients and bioactives to the brain in aging models in rodents. Determine the mechanisms related to the behavioral effects of nutrients and bioactives on biomarkers of inflammation and oxidative response. Objective 2: Characterize molecular, cellular, and physiological mechanisms by which food and nutritional factors affect the Central Nervous System regulation of aging processes and energy homeostasis. Sub-objective 2A: Assess whether age-related inflammation affects the cell genesis and cellular structure of the hypothalamus. Sub-objective 2B: Evaluate whether dietary intervention and natural products can be used to counteract age-related biochemical and structural changes in the hypothalamus. Sub-objective 2C: Assess whether dietary/natural product intervention attenuates systemic aging.

Approach
This project will utilize in vitro and in vivo studies on the mechanisms of action of nutrients and bioactives in improving brain function during aging. In particular, with a focus on age-related cognitive decline, including that associated with Alzheimer’s Disease, two objectives will focus on 1. The effects of genetic, metabolic, and environmental influences on the aging brain and vasculature and the modifying impact of nutrition on neuronal function, cognition, and behavioral outcomes. In addition to human observational data, cell and animal models will help resolve mechanisms underlying the benefits of nutrients and bioactives in the aging brain using rodent models. These studies will rely on inflammatory and oxidative stress molecular biomarkers as read outs of the preventative and potential disease attenuating attributes of diet and nutrition; and, 2. The characterization of molecular, cellular and physiological mechanisms by which food and particular combinations of phytocompounds act as nutritional and disease preventing/ treating factors for the aging central nervous system. In particular, the testing of a new theory of interactive brain and body aging will define age-related inflammation effects on cell genesis and cellular structure of the hypothalamus. In all, the studies proposed here, utilizing state of the art genetic, molecular, cellular and behavioral methodologies, will elucidate whether and how dietary/natural product intervention attenuates negative aspects of systemic aging.

Progress Report
The Neuroscience and Aging Laboratory seeks to identify applications of nutrition-based preventatives and therapeutics for reversing or slowing age-associated cognitive decline, neoplastic disorders and neurodegenerative disorders using an integrative approach of cellular, animal and human models. This translational research takes findings from basic science to design human intervention studies as the next step toward the real-world applications benefiting human health and quality of life. For studies related to Objective 1, clinical studies were performed to investigate effects of interventions with whole foods, including berries, almonds, or avocados, on cognition and motor performance. We found that supplementation increased cognitive function in healthy older adults, but motor performance was not improved. To examine how polyphenols in blueberries and strawberries were absorbed and whether absorption was related to cognition, we measured circulating levels of polyphenolics (anthocyanins, ellagitannins, and phenolic acids) in plasma. We found that the polyphenols were absorbed and extensively metabolized, resulting in the production of phenolic acid derivatives and their conjugates. Regular consumption of blueberries or strawberries led to berry-specific increases in circulating polyphenolics, improvements in cognition, and retention of some compounds in circulation. Therefore, addition of achievable quantities of berry fruit to the diets of older adults can improve cognition; this improvement is likely due to increased levels and persistence of circulating berry phenolics and their metabolites. Radiation exposure can cause long-term damage to the brain due to oxidative stress and inflammation; it is unknown if this exposure needs to occur directly to the brain or if hits restricted to the body will also cause damage. We showed that radiation exposures restricted to the body can disrupt neuronal function, as some measures of oxidative stress and inflammation in the brain were affected by body-only radiation; other measures showed greater change following whole-body (including brain) exposures. Oxidative stress and inflammation seem to be critical factors in these neuromodulatory changes, and in the behavioral disruptions seen following irradiation with cosmic rays. We initiated a study using a rat model of aging to evaluate the beneficial effects of wild blueberries on motor and cognitive function relative to the distribution of blueberry metabolites within the brain and the frequency of blueberry consumption. Previous studies from our laboratory have shown that continuous daily consumption of blueberry improved age-related declines in motor and cognitive function in old animals; however, the optimal intake of blueberries is unknown. Preliminary results showed that continuous blueberry-fed rats performed better on motor tasks and committed fewer errors in the radial arm water maze compared to control-fed animals. The intermittent-fed blueberry group had some positive effects, but did not perform as well as the continuous-fed blueberry group. Studies under Objective 2 examine the mechanisms of combined bioactive nutrient compounds to provide insights into molecular pathways that help to prevent and treat age-related neurological disease. We investigated the ability of the polymolecular botanical compound (PBC) from green tea, turmeric and broccoli sprouts to attenuate biomarkers of inflammation using cell and animal models. We confirmed that the polyphenolics from both blueberries and PBC could enhance calcium buffering in neurons and/or reduce stress signaling in microglia. Using human neural stem/progenitor cells derived from Parkinson’s patients and normal controls, we tested the effects of the PBC and blueberry extracts on progenitor cells’ viability, proliferation and differentiation. Polyphenol-rich berry extracts showed beneficial effects on the viability and proliferation of both control and Parkinson’s adult human neural progenitor cells and conferred a neuroprotective effect on these cells. On the other hand, the PBC and its individual components showed no significant effects on the stem/progenitor cells. However, they did demonstrate neuroprotection for these cells following induced cellular stress. In both studies, the individual components of the PBC were not as effective as the whole compound, indicating that individual polyphenols may be acting synergistically or exerting their effects through different and/or independent mechanisms. We also performed an animal study to investigate whether consumption of a PBC-supplemented high-fat diet could mitigate the brain alterations and behavioral dysfunction associated with a high-fat diet. Animals fed with a high-fat diet and high-fat diet+ PBC underwent behavioral tests to examine object recognition learning and memory. Brain tissue samples were collected for generation of neural stem cell cultures, and for neurosphere assays. Analyses are ongoing to evaluate effects of PBC on proliferation, inflammatory markers, and phenotyping of neuronal cells in various brain regions. Methods were developed to identify the tissue distribution of PBC administered to mice. Preliminary results demonstrated bioavailability of the polymolecular phytonutrients in peripheral mouse tissues, and studies on brain samples from these animals are underway. Therefore, dietary intervention with compounds such as those found in blueberries, green tea, turmeric, or broccoli sprouts could play a role in reducing the age-related brain inflammatory pathways that reduce neurogenesis and impair cognitive function. These foods could represent an adjunctive therapeutic strategy in the prevention and treatment of several neurodegenerative diseases, as well as other age-related brain dysfunctions. We are utilizing new cellular bioassays and sensitive biomarkers (exosomes/microvesicles) to monitor age-related neurological disease to investigate the roles for diet and nutrition in supporting healthy brain aging. Mechanisms of action of individual and combination phytonutrients are elucidated using cell cultures and personalized food and medicine animal models. A paper has been submitted for publication that describes exosomes/microvesicles as biomarkers in early-stage neurodegenerative disease by molecularly profiling neurogenesis- and chronic inflammation-associated exosomal cargoes in anticipation of using these readouts following nutrient testing of at-risk human neural stem/progenitor cells. A study has culminated and follow-up experiments are beginning that uncover an infectious disease component of neurological diseases that can accompany pathological aging. Working with an international group of collaborators on a large cohort of toxoplasma gondii infected patients, we revealed genetic networks altered by infection that are involved in epilepsy, Alzheimer’s and Parkinson’s disease, and cancer. The extensive omics data from this study will continue to be used to help guide our nutrient targeting of at-risk pathways following pathogenic infections that can hijack the brain’s connectome involved in memory, movement and other functions.

Accomplishments
1. Eating a variety of berries can improve brain functions in older adults. As people age, their cognitive functions – including memory, processing speed, executive function, and spatial learning – also decrease. ARS and ARS-funded researchers in Boston, Massachusetts have shown that eating polyphenol-rich berries such as strawberries and blueberries, can prevent and even reverse age-related cognitive decline. Different berries may produce different benefits due to their unique makeup and in what area of the brain they might be exerting their positive effects. For instance, researchers observed that strawberries can improve verbal and spatial memory, while blueberries can improve executive function and mental flexibility. Therefore, the researchers found that people should eat a variety of berries to experience maximum benefit to prevent decline in important brain functions.

Review Publications
Spencer, S.J., Korosi, A., Laye, S., Shukitt Hale, B., Barrientos, R.M. 2017. Food for thought: how diet influences cognitive function and emotion. NPJ Science of Food. 1(7). https://doi.org/10.1038/s41538-017-0008-y.
Sandhu, A.K., Miller, M.G., Thangthaeng, N., Scott, T.M., Shukitt Hale, B., Edirisinghe, I., Burton-Freeman, B. 2018. Metabolic fate of strawberry polyphenols after chronic intake in healthy older adults. Food & Function. 9:96-106.
Poulose, S.M., Miller, M.G., Scott, T., Shukitt Hale, B. 2017. Nutritional factors affecting adult neurogenesis and cognitive function. Advances in Nutrition. 8:804-811.
Scott, T., D'Anci, K.E., Rosenberg, I.H. 2017. B vitamins influence vascular cognitive impairment. In: Bendich, A., Deckelbaum, R.J., editors. Preventive Nutrition: The Comprehensive Guide for Health Professionals. 5th edition. Basel, Switzerland: Springer International Publishing. p. 309-318.
Steindler, D., Reynolds, B.A. 2017. Perspective: neuroregenerative nutrition. Advances in Nutrition. 8:546-557.
Roe, A.J., Zhang, S., Bhadelia, R.A., Johnson, E.J., Lichtenstein, A.H., Rogers, G.T., Rosenberg, I.H., Smith, C.E., Zeisel, S.E., Scott, T. 2017. Choline and its metabolites are differently associated with cardiometabolic risk factors, cardiovascular history and MRI documented cerebrovascular disease in older adults. American Journal of Clinical Nutrition. 105:1283-1290. https://doi.org/10.3945/ajcn.116.137158.
Chow, K., Park, H., George, J., Yamamoto, K., Gallup, A.D., Graber, J., Chen, Y., Jiang, W., Steindler, D., Neilson, E.G., Kim, B.G., Yun, K. 2017. S100A4 is a biomarker and regulator of glioma stem cells that is critical for mesenchymal transition in glioblastoma. Cancer Research. https://doi.org/10.1158/0008-5472.CAN-17-1294.
Shukitt Hale, B., Thangthaeng, N., Kelly, M.E., Smith, D.E., Miller, M.G. 2017. Raspberry differentially improves age-related declines in psychomotor function dependent on baseline motor ability. Food & Function. 8:4752-4759. http://dx.doi.org/10.1039/c7fo00894e.
Thangthaeng, N., Poulose, S., Fisher, D.R., Shukitt Hale, B. 2017. Walnut extract modulates activation of microglia through alteration in intracellular calcium concentration. Nutrition Research. 49:88-95. https://doi.org/10.1016/j.nutres.2017.10.016.
Carey, A.N., Gildawie, K.R., Rovnak, A., Thangthaeng, N., Fisher, D.R., Shukitt Hale, B. 2017. Blueberry supplementation attenuates microglia activation and increases neuroplasticity in mice consuming a high fat diet. Nutritional Neuroscience. https://doi.org/10.1080/1028415X.2017.1411875.
Rabin, B.M., Carrihill-Knoll, K.L., Miller, M.G., Shukitt Hale, B. 2018. Age as a factor in the responsiveness of the organism to the disruption of cognitive performance by exposure to HZE particles differing in linear energy transfer. Life Sciences in Space Research. 16:84-92. https://doi.org/10.1016/j.lssr.2017.12.001.
Reinartz, R., Wang, S., Kebir, S., Silver, D.J., Wieland, A., Zheng, T., Kupper, M., Rauschenbach, L., Fimmers, R., Shepherd, T.M., Trageser, D., Till, A., Schafer, N., Glas, M., Hillmer, A.M., Cichon, S., Smith, A.A., Pietsch, T., Liu, Y., Reynolds, B.A., Yachnis, A., Pincus, D.W., Simon, M., Brustle, O., Steindler, D., Scheffler, B. 2016. Functional subclone profiling for prediction of treatment-induced intratumor population shifts and discovery of rational drug combinations in human glioblastoma. Clinical Cancer Research. 23(2):562-574. https://doi.org/10.1158/1078-0432.CCR-15-2089.
Ngo, H.M., Zhou, Y., Lorenzi, H., Wang, K., Kim, T., Zhou, Y., El Bissati, K., Mui, E., Fraczek, L., Rajagopala, S.V., Roberts, C.W., Henriquez, F.L., Montpetit, A., Blackwell, J.M., Jamieson, S.E., Wheeler, K., Begeman, I.J., Naranjo-Galvis, C., Alliey-Rodriguez, N., Davis, R.G., Soroceanu, L., Cobbs, C., Steindler, D., Boyer, K., Noble, A., Swisher, C.N., Heydemann, P.T., Rabiah, P., Withers, S., Soteropoulos, P., Hood, L., McLeod, R. 2017. Toxoplasma modulates signature pathways of human epilepsy, neurodegeneration and cancer. Scientific Reports. 7(1):11496. https://doi.org/10.1038/s41598-017-10675-6.