Location: Jean Mayer Human Nutrition Research Center On Aging
Project Number: 8050-51000-102-000-D
Project Type: In-House Appropriated
Start Date: May 16, 2019
End Date: Mar 11, 2024
Objective:
Objective 1: Determine the effects of genetic, molecular and environmental influences on the aging brain, and the modifying impact of specific phytonutrients on neural cell function and behavior, including cognition.
Sub-Objective 1a: Characterize genetic and molecular signatures, especially pro-inflammatory markers, of normal adult brain stem/progenitor and differentiated cells, including neurons and microglia, in vitro and following the introduction of whole berry fruits and a combination phytonutrient: polymolecular botanical compound (PBC).
Sub-Objective 1b: Characterize genetic and molecular signatures of normal neural stem/progenitor and differentiated cells from Sub-Objective 1a in vivo following their grafting to the forebrains of immunocompromised mice, and subsequent feeding of the phytonutrients assayed in the in vitro model of Sub-Objective 1a.
Sub-Objective 1c: Characterize the genetic and molecular signatures, especially those associated with chronic inflammatory pathways, and the cognitive behavioral profile in aging models in rodents following feeding of phytonutrient compounds studied in Sub-Objectives 1a and b.
Sub-Objective 1d: Analyze biomarkers, especially those related to chronic inflammation and the cognitive behavioral profile, from liquid biopsies (e.g., serum) collected in human studies following phytonutrient supplementation with the candidate fruit and plant compounds studied in Sub-Objectives 1a-c.
Objective 2: Characterize in vitro and in vivo models that manifest aspects of human age-related neurological diseases, such as Parkinson’s and Alzheimer’s disease, for screening combinations of phytonutrient that can prevent or delay chronic inflammation and other deleterious micro-environmental conditions that contribute to cell degeneration in the neurodegenerative disorders.
Sub-Objective 2a: Characterize, in vitro, the genetic and molecular signatures, especially those associated with chronic inflammatory pathways, of stem/progenitor and differentiated neural and microglial cells (and exosomes isolated from them) isolated from patients with Parkinson’s Disease, following phytonutrient treatments studied in Objective 1.
Sub-Objective 2b: Characterize, in vivo, the genetic and molecular signatures (including mutant LRRK2-associated inflammation, stem cell and cell death/protection gene pathways) of cells, and exosomes derived from them, following xenotransplantation to the forebrain of immunocompromised mice and feeding of the phytonutrients studied in Objective 1.
Sub-Objective 2c: Characterize the genetic and molecular signatures of neural cells at-risk for abnormal functioning and cell death in transgenic mouse models of Parkinson’s disease, including behavioral studies, following feeding of candidate phytonutrient compounds studied in Objective 1.
Approach:
As Americans are living longer, the incidence of age-related neurological disorders is a growing burden for older adults and the healthcare system. Our lab studies how plant-derived phytonutrients benefit the aging brain, especially in maintaining mobility and cognitive function and slowing the progression of neurological disease. Specifically, we look at the ways phytonutrients can counteract the changes in the aging brain that make it more susceptible to neurological disorders. We focus on the persistent activation of inflammatory pathways that reduce brain plasticity and, over time, contribute to destructive cellular changes which affect the nervous system’s functioning and ability to adapt to new experiences. We will analyze the anti-inflammatory properties of phytonutrient combinations and berries that contain numerous beneficial bioactives that target aging processes involving cellular communication and the propagation of disease. In vitro and in vivo bioassays utilizing human stem/progenitor cells and the brain’s innate immune cells, microglia, will be used to test combinations of phytonutrient components in normal aging and neuropathological models (i.e. Parkinson’s disease in the proposed studies here). Exosome microvesicles isolated from these assays are used as sensitive biomarkers for gene and protein expression patterns in interactive anti-inflammatory, neurogenic, and cell survival networks. Phytonutrient screening along with molecular and behavioral findings from cell culture, in vivo xenotransplantation, and human studies will establish phytonutrient effects that help counter neurodegeneration.
