Progress 06/11/15 to 05/15/19
Outputs
Progress Report Objectives (from AD-416): 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 (from AD-416): 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. This is the final report for the project 8050-51000-084-00D. Substantial results were realized over the 5 years of the project, as progress was made on both objectives and their sub-objectives. Under Objective 1A, researchers from the Neuroscience and Aging Lab have now completed research efforts directed to answer the question of how B vitamins, including folic acid and vitamin B 12, could contribute to the protection of the aging brain and prevention of cognitive decline, with emphasis on maintenance of a healthy cerebral vasculature. Researchers have also explored the pathogenetic pathway that links B vitamin insufficiency and elevated homocysteine to the competence of the vascular system in the brain. The most recent observations have demonstrated that cerebrovascular abnormalities, including small vessel infarct and white matter hyperintensities, as observed in a cohort of aging individuals by magnetic resonance imaging, were strongly associated with both elevated homocysteine blood levels and the form of cognitive impairment most attributable to changes in vascular competence: executive cognitive function. Under Objective 1B, researchers conducted several clinical trials to investigate the effects of interventions with whole foods on motor function and cognition. Overall, supplementation with these whole foods, including almonds, avocados, blueberries, and strawberries, increased cognitive function in healthy older adults. One of the most interesting results showed that berry fruit, which is high in polyphenolics, differentially improved age-associated neuronal and cognitive deficits, possibly due to the unique phytochemical makeup. These results also showed in what area of the brain the phytochemicals might be exerting their beneficial effects. Researchers have observed that strawberries can improve verbal and spatial memory, while blueberries can improve executive function and mental flexibility, aspects of cognition that rely on different brain regions. Under Objective 1C, several studies investigated the mechanisms behind the age-related improvements conferred by whole foods. Investigators in the Neuroscience Lab examined the mechanisms related to the behavioral effects of phytonutrients and bioactives, e.g., raspberries, blueberries, strawberries, acai berries, walnuts, and tart cherries, on biomarkers of inflammation and oxidative stress by using animal and cell models. Researchers found that polyphenols enhanced protective cellular communication (signaling), neuronal housekeeping (i.e., autophagy), and neuronal growth and showed that poor performers were the most likely to benefit from daily consumption of berries. Researchers in the lab found that polyphenols in walnuts, when fed to rats, can enhance brain DNA methylation patterns and increase expression of immediate-early genes in key brain regions, which are essential in memory formation and synaptic plasticity. Researchers also showed that pre-treatment with serum from rats fed these foods was efficacious in reducing inflammatory and oxidative stress signaling in a microglia cell model. Therefore, metabolites present in the circulating blood may be mediating the anti- inflammatory effects of foods. Additionally, using ground-based radiation animal models, researchers found that brain areas for memory are more sensitive to oxidative and inflammatory insults. When investigators supplemented, prior to radiation exposure, rodent diets with blueberries, which are known to contain high amounts of antioxidant-phytochemicals, researchers found that they could prevent these brain and behavioral changes. Under Objective 2A, researchers from the Neuroscience and Aging Lab investigated whether plant foods such as blueberry and epidiferphane, a combination of phytochemicals incorporating epigallocatechin gallate, curcumin, and sulforaphane from broccoli sprouts, can attenuate the inflammation and oxidative stress associated with aging and neurodegenerative disease, and at the same time support the growth and differentiation of human neural stem and progenitor cells. Data showed that epidiferphane, as well as its individual components, was able to lessen the decrease in cell viability as well as proliferation rate following cellular stress induced by dopamine, and synergetic effects from the whole compound appear to be more protective when compared to each of the individual components. Blueberries were also able to abrogate a decrease in cell viability, proliferation rate as well as the deficits in Ca2+ buffering following cellular stress induced by dopamine in adult human brain neural progenitor cells. Blueberries also reduced stress- mediated signaling in rat microglial cells and expression levels of certain oxidative stress and inflammation markers in human neural stem cells. Under Objective 2B, researchers characterized exosomes isolated from human adult stem cells and human induced pluripotent stem cells (hiPSCs)- generated dopamine neurons of a LRRK2 gene-identified Parkinson⿿s patient. Researchers found that exosomes derived from patients with LRRK2 gene mutation look different and contain disease- and inflammation-related molecular profiles amenable to gene correction. Investigators have also shown that xenografted hiPS cells can survive, migrate, and differentiate in immune deficient mice, functionally integrate within host brain circuitry, and thus provide a potential reliable model for testing long- term central nervous system therapeutic outcomes of a variety of nutrient and other bioactive compounds. Under Objective 2C, researchers began an animal study to examine the mechanisms related to the behavioral effects of nutrients and bioactives, specifically epidiferphane, on neurogenesis and inflammation. Long-term consumption of a high fat diet has been shown to increase inflammation and oxidative stress in the brains of rodents, and it also produces behavioral deficits. Researchers initiated an animal study to see if epidiferphane, a combination of antioxidant and anti-inflammatory phytochemicals, could mitigate the mouse brain alterations and behavioral dysfunction associated with high fat diets. The effects of epidiferphane on proliferation, inflammatory markers, and phenotyping of the brain cells in various brain regions are currently being evaluated. Researchers have also developed methods and identified the tissue distribution of curcumin and epigallocatechin gallate in tissues from animals fed with epidiferphane. Tissue samples from liver, kidney, heart, lungs and brain (using Liquid Chromatography-Mass Spectrometry methods) were processed for high-performance liquid chromatography analysis for these compounds and related metabolites. Despite the need for continuing analyses, preliminary data has already shown the bioavailability of this orally administered EDP in mouse tissues. Blueberries reduce inflammation in brain and slow Parkinson⿿s disease growth. The aging process impacts neural stem cells and affects their ability to function properly, which ultimately can lead to cell death, loss of a cell⿿s power to grow and divide, or loss of regenerative potential. This aging-induced decline in the growth and development of nervous tissue and deterioration of stem cell functions may play a key role in the processes of various aging-associated disorders and neuronal dysfunctions. ARS and ARS funded researchers in Boston, Massachusetts studied adult human neural stem/progenitor cells, which are important to the nervous system because they can grow into specific cells. These cells were derived from both normal subjects and Parkinson⿿s patients. Researchers evaluated the possible beneficial effects of nutrients, e.g., polyphenol-rich blueberry extracts, on human neural stem cells from the hippocampus region, which is associated with memory. The data indicated that blueberries slow the growth of Parkinson⿿s disease adult human neural stem/progenitor cells in the memory region of the brain⿿a region affected by Parkinson⿿s. Researchers also investigated the potential cellular and molecular mechanisms underlying the beneficial effects of blueberries on adult human neural stem/progenitor cells and found that blueberry extract treatments were able to decrease the expression levels of biomarkers of oxidative stress and inflammation compared to non- treated cells. Therefore, blueberry extracts may provide anti-oxidative and anti-inflammatory benefits on adult human neural stem/progenitor cells and thus can help prevent neural cell loss and dysfunctions during aging. This suggests an important dietary role for nutrients in helping to prevent and slow progression of aging and neurodegenerative diseases.
Impacts
(N/A)
Publications
- Shukitt Hale, B., Nopporn, T., Miller, M.G., Poulose, S.M., Fisher, D.R. 2019. Blueberries improve neuroinflammation and cognition differentially depending on individual cognitive baseline status. Journal of Gerontology Biological Science.
- Rabin, B.M., Poulose, S.M., Bielinski, D.F., Shukitt Hale, B. 2019. Effects of head-only or whole-body exposure to very low doses of 4He (1000 MeV/n) particles on neuronal function and cognitive performance. Life Sciences in Space Research. 20:85-92.
- Scott, T., Bhadelia, R.A., Qiu, W., Folstein, M.F., Rosenberg, I.H. 2018. Small vessel cerebrovascular pathology identified by magnetic resonance imaging is prevalent in Alzheimer's disease and mild cognitive impairment: a potential target for intervention. Journal of Alzheimer's Disease. 65(1) :293-302.
- Rosenberg, I.H., Selhub, J. 2018. Assessing all the Evidence for Risks and Benefits With Folic Acid Fortification and Supplementation. In: Mannar, V. M.G., Hurrell, R.F., editors. Food Fortification in a Globalized World. Cambridge, MA: Academic Press. p. 241-246.
- Siebzehnruebl, F.A., Raber, K.A., Urbach, Y.K., Schulze-Krebs, A., Canneva, F., Moceri, S., Habermeyer, J., Achoui, D., Gupta, B., Steindler, D.A., Stephan, M., Nguyen, H., Bonin, M., Riess, O., Bauer, A., Aigner, L., Couillard-Despres, S., Paucar, M.A., Svenningsson, P., Osmand, A., Andreew, A., Zabel, C., Weiss, A., Kuhn, R., Moussaoui, S., Blockx, I., Van Der Linden, A., Cheong, R.Y., Roybon, L., Petersen, A., Van Hoersten, S. 2018. Early postnatal behavioral, cellular, and molecular changes in models of Huntington disease are reversible by HDAC inhibition. Proceedings of the National Academy of Sciences. 115(37):E8765-E8774.
- Gildawie, K.R., Galli, R.L., Shukitt Hale, B., Carey, A.N. 2018. Protective effects of foods containing flavonoids on age-related cognitive decline. Current Nutrition Reports.
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Progress 10/01/17 to 09/30/18
Outputs
Progress Report Objectives (from AD-416): 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 (from AD-416): 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. 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 01 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.
Impacts
(N/A)
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).
- 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., DAnci, 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
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Progress 10/01/16 to 09/30/17
Outputs
Progress Report Objectives (from AD-416): 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 (from AD-416): 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. The Neuroscience and Aging Laboratory seeks to identify applications of nutrition-based preventatives and therapeutics for reversing or slowing age-associated cognitive decline, neurodegenerative disorders and age- related brain neoplastic 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 towards the goal of real-world applications benefiting human health and quality of life. Studies related to Objective 1, are being completed for clinical studies investigating the effects of intervention with whole foods � such as blueberries, strawberries, and avocados � on cognitive outcomes and have found that supplementation with these foods increased cognitive function in healthy older adults. To examine how polyphenols in blueberries and strawberries were absorbed and whether this absorption was related to cognition, we measured circulating levels of polyphenolics in plasma, including anthocyanins, ellagitannins, and phenolic acids, after an overnight fast and 2 hours postprandial. We found that these compounds were significantly altered as a result of berry consumption, as the polyphenols were absorbed and extensively metabolized, resulting in the production of various phenolic acid derivatives and their conjugates. Additionally, changes in circulating levels of specific phenolic compounds were correlated with the observed changes in cognition. Therefore, the addition of easily achievable quantities of berry fruit to the diets of older adults can improve some aspects of cognition, which is likely due to increased levels of circulating berry phenolics and their metabolites. Studies are underway for Objective 2 to examine the mechanisms of combined bioactive nutrient compounds to provide insights into diet and nutrient molecular pathways that help to prevent and treat age-related neurological disease. The first proof of principle is the compound EpidiferphaneTM (EDP) and its ability to attenuate biomarkers of inflammation using cell and animal models. At least part of the loss of cognitive function in aging may be dependent upon a dysregulation in calcium homeostasis, and this loss affects numerous signaling pathways. We conducted a study to examine whether the polyphenolics from blueberries (BB) or EpidiferphaneTM (EDP,) a combination of phytochemicals incorporating green tea catechin (epigallocatechin gallate, EGCG,) curcumin from turmeric, and broccoli sprouts which contain the isothiocyanate sulforaphane, could enhance calcium buffering in neurons and/or reduce stress signaling in microglial cells. Both BB and EDP were able to protect against deficits in calcium buffering induced by a dopamine stressor, showing that pre-treatment with these compounds can reduce both stress- and inflammatory-induced neuronal dysfunction. Additionally, human neural stem/progenitor cell models, including cells derived from Parkinson�s and Alzheimer�s patients and normal controls, are being established in the lab. We utilized these in vitro models for testing the effects of EDP and second, third, etc. generation combinations of whole food-derived nutrients on progenitor cells� viability, proliferation and differentiation. While EDP as well as its individual components did not show significant effects on viability, proliferation and differentiation of adult human neural progenitor cells, �AHNPs,� that we discovered in the human brain gray matter throughout the lifespan, they did demonstrate neuroprotection for the AHNPs following cellular stress induced by a dopamine stressor. In both studies, the individual components of EDP were not as effective as the whole compound, showing that the individual polyphenols in the different components may be acting synergistically or exerting their effects through different and/ or independent mechanisms. Dietary blueberry also attenuated radiation- induced declines in protein carbonyl content, a marker for oxidative protein degradation, as well as reduced the oxidative and inflammatory load, and enhanced endogenous protective signaling. Therefore, dietary intervention with compounds such as those found in blueberries, green tea, turmeric, or broccoli sprouts can play a role in reducing the age- related central nervous system inflammation, microglial activation, and stimulation of immune pathways that reduce neurogenesis and impair cognitive function. Additionally, we began an animal study to examine the mechanisms related to the behavioral effects of nutrients and bioactives, specifically EDP as our first generation of polymolecular botanical compound combinations, on biomarkers of inflammation. Long-term consumption of a high fat diet (HFD) has been shown to increase inflammation and oxidative stress (OS) in the brains of rodents, and consumption of a HFD produces behavioral deficits. We initiated a study to see if Epidiferphane� (EDP,) a combination of antioxidant and anti-inflammatory phytochemicals, could combat the negative effects of a HFD by decreasing inflammation and OS. Therefore, the goal of this study is to show whether consumption of an EDP-supplemented HFD will mitigate the brain alterations and behavioral dysfunction associated with HFD. Additionally, we completed two studies using tart cherries, which are high in polyphenols. Tart cherries improved cognitive behavior in aged rats and were efficacious in reducing inflammatory and OS signaling in a microglia cell model. This protection might be one mechanism by which dietary supplementation of tart cherries can improve age-related deficits in behavioral and neuronal functioning. We have also established protocols to analyze the bioavailability of EDP as well as their individual components in both in-vivo and in-vitro cell culture studies. For in vivo studies, animals were fed with EDP daily for about 12 weeks. At the end of the feeding period, the animals were sacrificed, and their tissues such as liver, kidney, spleen, brain, serum, heart and lungs were collected and stored. Individual components of EDP were extracted for HPLC (high-performance liquid chromatography) analysis to identify the bioavailability of EDP�s principle bioactive components. For in vitro studies, AHNPs were harvested following a 4-day treatment of EDP, and concentration of components of EDP were examined in the cell lysates. Optimized detection methods were successfully developed and significantly reduced the time to run each sample as well the solvents required. With these methods, the concentrations of curcumin and ECGC were detected both in liver as well as kidney tissues, indicating the relatively high bioavailability of these compounds. These findings support the role of diet in combatting the negative effects of exposure to inflammation and oxidative stress through the consumption of polyphenolic-rich and omics-informed anti-inflammatory network foods. A notion of neuroregenerative nutrition is a focus of new bioassays for our lab. With both in vitro and in vivo models of age-related neurological disease, including cellular components that are both at-risk in neurodegenerative disease and brain cancer, along with patient-matched immune cells, stem cell biology is being used as a major focus for combining foods and particular nutrients that can counteract the loss of cellular potency and plasticity associated with a chronic inflammatory tissue microenvironment that accompanies pathological aging, diseases and injuries, as well as standard of care therapies. It is anticipated that our new bioassays and molecular biomarkers for monitoring age-related neurological disease will provide essential data on the roles for diet and nutrition in supporting healthy brain aging and cognitive function in the later third of life. We now have new cellular reagents under development that best reflect the at-risk cellular components of Alzheimer�s Disease: the brain�s innate immune cells, microglia. Using state-of-the-art induced pluripotent stem cells derived from Alzheimer�s versus control skin fibroblasts, microglia are being generated in collaboration with the Massachusetts Institute of Technology-Whitehead Institute that will provide a sensitive and accurate disease target for reducing chronic inflammation as a result of assaying next generation polymolecular botanical food compounds. These compounds are in combinations that target inflammatory pathways that interfere with stem cell repair and regeneration in the brain and other organs and tissues. We are studying the relationship between brain and body aging in ways where nutrient combinations hold promise for supporting the best cell and tissue health. Next generations of EDP are currently under consideration for analysis for a variety of age-related neurological diseases, including Parkinson�s, where stem cell pathologies are potent targets of nutrient preventative and treatment therapies. Mechanisms of action of individual and combination phytonutrients will be elucidated using our next generation cell/organoid/cultures and personalized, precision food and medicine animal models. Using exosomes/microvesicles as the most sensitive biomarkers of disease state and response to standard of care and integrated medicine therapies and preventatives, current studies focus on the roles of diet and nutrient supplementation to reverse chronic inflammatory gene and protein networks involved in susceptibility to age-related neurological disease and progression once disease has passed the prodromal stage.
Impacts
(N/A)
Publications
- Poulose, S.M., Rabin, B.M., Bielinski, D.F., Kelly, M.E., Miller, M.G., Thangthaeng, N., Shukitt Hale, B. 2017. Neurochemical differences in learning and memory paradigms among rats supplemented with anthocyanin- rich blueberry diets and exposed to acute doses of 56Fe particles. Life Sciences in Space Research. 12:16-23.
- Miller, M.G., Thangthaeng, N., Poulose, S.M., Shukitt Hale, B. 2017. Role of fruits, nuts, and vegetables in maintaining cognitive health. Experimental Gerontology. 94:24-28. doi: 10.1016/j.exger.2016.12.014.
- Carey, A., Miller, M.G., Fisher, D.R., Bielinski, D., Gilman, C.K., Poulose, S.M., Shukitt Hale, B. 2017. Dietary supplementation with the polyphenol-rich a�a� pulps (Euterpe oleracea Mart. and Euterpe precatoria Mart.) improves cognition in aged rats and attenuates inflammatory signaling in BV-2 microglial cells. Nutritional Neuroscience. 20:238-245.
- Miller, M.G., Hamilton, D.A., Joseph, J.A., Shukitt Hale, B. 2017. Dietary blueberry improves cognition among older adults in a randomized, double- blind, placebo-controlled trial. European Journal of Nutrition. doi: 10. 1007/s00394-017-1400-8.
- Miller, M.G., Thangthaeng, N., Shukitt Hale, B. 2017. A clinically relevant frailty index for aging rats. Journal of Gerontology, Series A, Biological Sciences and Medical Sciences. doi:10.1093/gerona/glw338.
- Thangthaeng, N., Miller, M., Gomes, S., Shukitt Hale, B. 2015. Daily supplementation with mushroom (Agaricus bisporus) improves balance and working memory in aged rats. Nutrition Research. 35:1079-1084.
- Poulose, S.M., Bielinski, D.F., Carey, A., Schauss, A.G., Shukitt Hale, B. 2016. Modulation of oxidative stress, inflammation, autophagy and expression of Nrf2 in hippocampus and frontal cortex of rats fed with acai- enriched diets. Nutritional Neuroscience. doi: 10.1080/1028415X.2015. 1125654.
- Thangthaeng, N., Poulose, S., Gomes, S.M., Miller, M.G., Bielinski, D., Shukitt Hale, B. 2016. Tart cherry supplementation improves working memory, hippocampal inflammation and autophagy in aged rats. Age. 38:393-404. doi: 10.1007/s11357-016-9945-7.
- Wong, J.C., Scott, T., Wilde, P., Li, Y., Tucker, K., Gao, Z. 2016. Food insecurity is associated with subsequent cognitive decline in the Boston Puerto Rican Health Study. Journal of Nutrition. doi: 10.3945/jn.115. 228700.
- Scott, T., Rogers, G., Weiner, D.E., Livingston, K., Selhub, J., Jacques, P.F., Rosenberg, I.H., Troen, A. 2017. B-vitamin therapy for kidney transplant recipients lowers homocysteine and improves selective cognitive outcomes in the randomized FAVORIT ancillary cognitive trial. The Journal of Prevention of Alzheimer's Disease. 3:1-9.
- Shukitt Hale, B., Kelly, M.E., Bielinski, D.F., Fisher, D.R. 2016. Tart cherry extracts reduce inflammatory and oxidative stress signaling in microglial cells. Antioxidants. doi: 10.3390/antiox5040033.
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Progress 10/01/15 to 09/30/16
Outputs
Progress Report Objectives (from AD-416): 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 (from AD-416): 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. The Neuroscience and Aging Laboratory seeks to identify applications of nutrition-based therapeutics for reversing or slowing age-associated cognitive decline 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 towards the goal of real-world applications benefiting human health and quality of life. Through continuing secondary analysis of the Nutrition, Aging, and Memory in the Elderly (NAME) study, we have found that nutrients that are essential during child development may have a more complicated impact in aging adults. Choline is a nutrient necessary for the structural integrity of, and communication between, neurons (brain cells), and is essential to neurodevelopment. However, there are also a number of potential links between choline and risk for vascular and heart disease through its role in lipid and one-carbon metabolism. Our data have shown that participants with the highest levels of choline concentrations in their blood had higher odds of having a history of cardiovascular disease and large blood vessel infarcts (strokes) in the brain, but had lower odds of small blood vessel disease. These findings that choline and its metabolites had differing associations with risk factors for heart disease and subtypes of cerebrovascular disease suggest differing roles in the disease process of cardiovascular and cerebral (brain) large vessel disease versus small vessel disease. We continue to evaluate whether a person�s genetic makeup affects how choline is used in the body and its relationship with these outcome measures. We have also continued to analyze our rich dataset from the Boston Puerto Rican Health Study, a study funded to investigate disparities in health-related outcomes including cognitive function. Most recently we�ve found that there is a high prevalence of food insecurity (living with hunger and fear of not having enough food) in our cohort of Hispanics living in the Boston area, and that those participants with higher levels of food insecurity were more likely to experience cognitive decline over a two-year period of time. We recently completed commodity-board funded clinical studies investigating the effects of intervention with whole foods � such as avocadoes and strawberries � on biomarkers of, inflammation, and oxidative stress and the relationship with cognitive outcomes. We found that daily intake of avocadoes improved working memory, but we did not find an effect of avocado consumption on measures of inflammation or oxidative stress, although those participants with biomarkers showing the least resistance to oxidative stress at baseline declined in cognitive function over the 6 month duration of the study. In another study, we found that dietary supplementation with 2 cups of strawberry increased word recognition and improved spatial memory in older adults. Strawberry had no effect on mobility among this population of healthy older adults. Therefore, including berry fruit and avocados in the diet of healthy older adults may be one means of combating some age-related functional declines. We examined the mechanisms related to the behavioral effects of nutrients and bioactives, i.e, raspberries, blueberries, and walnuts, on biomarkers of inflammation and oxidative stress by using animal and cell models. While polyphenolic compounds found in these foods may have direct effects on oxidative stress and inflammation in aging, they also may enhance protective cellular communication (signaling), neuronal housekeeping (i.e., autophagy, a process by which toxic debris is recycled and cleared in neurons), and neuronal growth. We tested whether supplementation with raspberries, a fruit high in polyphenols, could forestall and reverse the deleterious effects of aging on motor and cognitive behavior in rodents, and whether or not baseline performance was a factor in these improvements. Results showed that poor performers were the most likely to benefit from daily consumption of �-1 cup of raspberries by improving/preserving motor function. Therefore, eating raspberries may reduce fall risk, extend independence, and improve quality of life in the aging population. We also studied the molecular and genetic mechanisms responsible for the beneficial effects of walnuts and blueberries, and whether metabolites from these foods would also provide beneficial effects, using brain cell (in vitro) and animal models. We found that polyphenols in walnuts, when supplemented in a rat diet, can enhance brain DNA methylation patterns and increase expression of immediate-early genes in key brain regions, which are essential in memory formation and synaptic plasticity. We also showed that serum from humans or rats fed blueberries protected brain cells in culture against stresses by attenuating oxidative stress and inflammation. Additionally, human neural stem/progenitor cell models, including cells derived from Parkinson�s patients as well as normal controls, have been established in the lab. Effects of individual nutrient supplements such as Epigallocatechin gallate (EGCG), curcumin, sulforaphane from broccoli sprouts, as well as their synergistic effects (EDP) on cell proliferation, cell death and cell differentiation are being investigated using these cellular assays. Dietary blueberry also attenuated radiation-induced declines in protein carbonyl content, a marker for oxidative protein degradation, as well as reduced the oxidative and inflammatory load, and enhanced endogenous protective signaling. These findings support the role of diet in combatting the negative effects of exposure to inflammation and oxidative stress through the consumption of polyphenolic-rich foods such as berries and nuts. Accomplishments 01 Dietary blueberry improves cognition among older adults in a randomized, double-blind, placebo-controlled trial. As populations shift to include a larger proportion of older adults, the necessity of research targeting older populations is becoming increasingly apparent. Dietary interventions with blueberry have been associated with positive outcomes in cell and rodent models of aging. This study investigated whether dietary blueberry would improve mobility and cognition among older adults. ARS and Tufts University researchers at USDA in Boston, Massachusetts, studied men and women between the ages of 60 and 75 years who consumed freeze-dried blueberry (24g/d, equivalent to 1 cup of fresh blueberries) or a blueberry placebo for 90 days. Participants completed balance, gait, and cognitive tests at baseline, 45 days and 90 days of intervention. Participants in the blueberry group showed significantly fewer repetition errors on a memory test and better performance on an executive function test, relative to controls. Therefore, these findings show that the addition of easily achievable quantities of blueberry to the diets of older adults can improve some aspects of cognition. 02 Dietary supplementation with the polyphenol-rich a�a� pulps improves cognition via modulation of oxidative and inflammatory brain signaling. A�a� (Euterpe spp.), a fruit rich in polyphenols, has emerged as a promising source of natural antioxidants with pharmacological and nutritional value. ARS and Tufts University researchers in Boston, Massachusetts, studied the age-related effects on brain health and cognition of two different species of a�a� pulp extracts, namely, Euterpe oleracea Mart. (EO) and Euterpe precatoria Mart. (EP). Our studies showed that after 8 weeks of dietary supplementation with 2% EO or EP, aged rats demonstrated improved working memory; however, only the EO diet improved reference memory. Our results also showed that cells treated with blood serum from acai-fed rats produced less oxidative and inflammatory markers (nitric oxide and tumor necrosis factor-alpha) than control-fed rats and the serum from rats with better cognitive performance had more protection against inflammatory signaling. Supplementation with acai also improved function in critical brain regions via upregulation of antioxidant enzymes, reduction of markers of reactive oxygen species and inflammation, and activation of the brain�s natural housekeeping function. These findings provide further support on the effects of a�a� dietary supplementation in critical brain regions, and provide information on mechanisms or processes by which polyphenol-rich foods may benefit memory, cognition, and overall brain function.
Impacts
(N/A)
Publications
- Rabin, B.M., Carrihihll-Knoll, K.L., Shukitt Hale, B. 2015. Comparison of the effectiveness of exposure to low LET helium particles (4He) and gamma rays (137Cs) on the disruption of cognitive performance. Radiation Research. 184:266-272.
- Poulose, S.M., Thangthaeng, N., Miller, M.G., Shukitt Hale, B. 2015. Effects of pterostilbene and resveratrol on brain and behavior. Neurochemistry International. 89:227-233.
- Thangthaeng, N., Poulose, S.M., Miller, M.G., Shukitt Hale, B. 2016. Preserving brain function in aging: the anti-glycative potential of berry fruit. NeuroMolecular Medicine. 18:465-473, doi: 10.1007/s12017-016-8400-3.
- Galli, R.L., Carey, A.N., Luskin, K.A., Bielinski, D.F., Shukitt Hale, B. 2016. Red raspberries can improve motor function in aged rats. Journal of Berry Research. 6:97-103.
- Shukitt Hale, B., Bielinski, D., Lau, F., Willis, L.M., Carey, A., Joseph, J. 2015. The beneficial effects of berries on cognition, motor behavior, and neuronal function in aging. British Journal of Nutrition. 114:1542�1549. doi:10.1017/S0007114515003451.
- Rabin, B.M., Poulose, S.M., Carrihill-Knoll, K.L., Ramirez, F., Bielinski, D.F., Heroux, N., Shukitt Hale, B. 2015. Acute effects of exposure to 56Fe and 16O particles on learning and memory. Radiation Research. 184:143-150.
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Progress 10/01/14 to 09/30/15
Outputs
Progress Report Objectives (from AD-416): 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 (from AD-416): 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. This new Project Plan was recently certified through ARS Office of Scientific Quality Review (OSQR) and will report progress in 2016. For further details on recent research effort see the 2015 report for project 8050-51000-081- 00D.
Impacts
(N/A)
Publications
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