1a. 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.
1b. 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.
3. Progress Report:
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 ½-1 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.
1. 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.
2. Dietary supplementation with the polyphenol-rich açaí pulps improves cognition via modulation of oxidative and inflammatory brain signaling. Açaí (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 açaí 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 açaí 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.
5. Significant Activities that Support Special Target Populations:
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.
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.