Location: Boston, Massachusetts2011 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
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. 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 also 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 or not whole foods were better than individual components, using brain cells (in vitro) and animal models. We showed that both acai fruit (and its individual components) and walnuts were able to rescue neurons through induction of autophagy, a process by which toxic debris is recycled and cleared in neurons. We continued studies showing that berry fruit, particularly acai, reduced oxidative stress and inflammation caused by chemicals, in different types of brain cells such as microglia, astrocytes, and neurons. The berries were able to protect neurons through auxiliary effects on astrocytes when they were co-cultured with the neurons, as they are in the brain. Additionally, we began to examine individual components from berry fruit and fatty acids from walnuts to determine which might be responsible for their beneficial effects. We showed that different components of the berries and walnuts were effective against inflammatory and oxidative stress in brain cells, although the whole fruit or nut was also effective, and not toxic like the individual components. Another study indicated that different components of blueberries (i.e., stilbenes and anthocyanins) were effective in preventing stress-induced calcium imbalance and inflammation, but the stilbenes were more effective than the anthocyanins. We continued to examine whether the specific polyphenolic components in the different berries work differentially to produce their beneficial effects. Using brain cells we carried out experiments to examine various treatment durations and doses for the blueberries (BBs) and strawberries (SBs), individually and in combination, on inflammatory markers to elucidate individual vs. synergistic effects. We found that in general, BB was more effective than SB and that combinations were not more effective than BB alone. In an animal study, we examined the effects of BB and SB or their combination on cognition and decreases in inflammation; this work is still ongoing. Therefore, it may be that the individual polyphenols in the different berries might exert their effects through different and/or independent mechanisms.
Malin, D.H., Lee, D.R., Goyarzu, P., Chang, Y., Ennis, L.J., Beckett, E., Shukitt Hale, B., Joseph, J.A. 2011. Short-term blueberry-enriched antioxidant diet prevents and reverses object recognition memory loss in aged rats. Nutrition. 27:338-342.