Location: Boston, Massachusetts2013 Annual Report
1a. Objectives (from AD-416):
LAB: Nutrition & Neurocognition 1. Determine the role of nutritional factors, especially B-vitamins and choline, in preventing age-related cognitive impairment using human intervention and population studies. 2. Characterize mechanisms by which nutritionally induced hyperhomocysteinemia affects neuronal function and cognitive performance using other animal models of human cognitive decline. LAB: Neuroscience 1. Use cell models to develop mechanistic interpretations of the positive benefits of berry polyphenols and fatty acids by examining their direct effects on deficits in stress and protective signaling. 2. Establish the effects of dietary berry fruit extracts and/or fatty acids on behavioral and neuronal deficits in aging to assess the mechanisms involved and the most effective polyphenols/fatty acids in animal and human models.
1b. Approach (from AD-416):
LAB: Nutrition & Neurocognition With the population aging, the imperativeness to understand and prevent age-related cognitive decline and disability grows more important. We approach this problem with nutritional studies in human populations and in studies of animal models. Observational and cohort studies in humans examine the association of modifiable nutritional factors especially B vitamins, vitamin D, and polyunsaturated fatty acids with the trajectory of cognitive decline and measurable brain volumes with age. Intervention studies with B vitamins to lower homocysteine levels in blood and protect against neurological and vascular degeneration examine our ability to delay cognitive decline, dementia, and disability. Genotyping focusing on methylation pathways provide insight into how genetic variability may modify or modulate the neurological response to nutrition and dietary factors. Animal models of aging and dementia are employed to examine the mechanism of nutritional modification of neural and cerebrovascular degeneration with effects on behavior. Rodents are made deficient in B vitamins or polyunsaturated fatty acids or choline and effects on brain function (behavior), brain biochemistry, and brain histology provide insights into pathways by which nutritional perturbations influence aging brain chemistry and function. LAB: Neuroscience The focus of the current project is to elucidate the mechanisms involved in the beneficial effects of berry fruit and polyunsaturated fatty acids (PUFAs) from fish or nut oils on reducing neurodegeneration mediated by oxidative stress (OS) and inflammation (INF). Mixed neuron/ glial cultures obtained from rats of different ages will be employed to delineate the neuroprotective effects of berry fruit or PUFA against OS/INF and subsequent stress mediated by glial cells. Additionally, muscarinic receptor-transfected COS-7 cells will be used to assess OS/INF localization and the effects of membrane lipids on the cellular responses to OS/INF. Extensive motor and cognitive assessments will also be made of senescent animals fed diets containing berry fruit or PUFAs. Finally, we will translate the behavioral findings obtained in our animal studies to the human condition by examining the effects of berry fruit or walnut supplementation on human gait and motor ability. This project will contribute to fundamental new knowledge of the putative role of berry fruit and PUFAs on reducing OS/INF and behavioral deficits in aging. These studies will span basic cellular signaling, animal behavior and cognition, and human motor abilities, allowing for a comprehensive examination of the beneficial effects of berry fruit and nutritional PUFAs on the aging brain.
3. Progress Report:
NEUROSCIENCE: We have shown that supplementation with fruits, vegetables, and nuts can forestall and reverse the deleterious effects of aging on neuronal (brain cell) functioning and behavior in rodents. While polyphenolic compounds found in these foods may have direct effects on oxidative stress (OS) and inflammation in aging, they also may enhance protective cellular communication (signaling), neuronal housekeeping (autophagy), and neuronal growth. Discovery of these additional mechanisms might lead to important dietary information for an aging population. Additionally, determining which components might be responsible for the beneficial effects is important, although it might be that the combination of polyphenols or fatty acids present in berries or nuts may have synergistic effects, which provide increased protection from age-related declines relative to individual constituent compounds. This year we continued to study the mechanisms responsible for the beneficial effects of berry fruit and fatty acids and whether metabolites from these foods would also provide beneficial effects, using brain cells (in vitro), animal models, and human studies. We showed that serum from rats fed walnuts, açaí fruit, strawberries, or blueberries protected brain cells in culture against stresses by attenuating OS and inflammation. Furthermore, reductions in inflammatory markers were correlated with improved behavior in aged rats. We continued to test several fruits/vegetables high in polyphenols for their beneficial effects in reversing age-related deficits in behavioral and brain function when fed to old rats. We fed aged animals different species of acai fruit, tart cherries, or mushrooms at various doses and tested the rats on a battery of motor and cognitive tests. These foods were able to protect against age-induced deficits in behavior and we are correlating these results with brain antioxidant and/or anti-inflammatory levels, as well as measures of signaling and autophagy (a process by which toxic debris is recycled and cleared in neurons), to understand the mechanisms of action through which the polyphenols in these foods could be producing their effects. We showed that two aging models that elicit inflammation and OS (exposure to cosmic rays and high-fat diets) caused decrements in cognition, gene expression, and autophagy, which were prevented by pre-feeding the animals with blueberry and/or strawberry diets. We also began a clinical study to examine the effects of feeding one cup of blueberries/day to adults 60-75 years of age on measures of gait, balance, and cognition.
Carey, A.N., Fisher, D.R., Joseph, J.J., Shukitt Hale, B. 2013. The ability of walnut extract and fatty acids to protect against the deleterious effects of oxidative stress and inflammation in hippocampal cells. Nutritional Neuroscience. 16(1):13-20.