Specific Pathogen Free Baboon Research Resource (SPFBRR) - Administrative Supplement (Epigenetic)

项目总结/文摘

Project Summary/Abstract Epigenetic age is a new, robust biomarker of aging that has outperformed other molecular and phenotypic biomarkers of aging in predicting morbidity and mortality. Epigenetic age is calculated using DNA methylation levels at specific sites in the genome to create a DNA methylation clock (DMC). The DMC is then used to find the deviation between an individual’s epigenetic age and chronological age, which determines whether the individual shows age-acceleration, which has been implicated in a host of age-related diseases, including AD/ADRD. However, DMCs have not been developed for baboons, a commonly-used animal model for various aging-related diseases. Given that baboons show hallmarks of AD neuropathy, there is a need for further development of the baboon as a model for aging and AD. The University of Texas MD Anderson Cancer Center (MDACC) is growing and maintaining the world’s only adventitious virus-free baboon breeding colony (Specific Pathogen Free Baboon Research Resource). Therefore, the proposed administrative supplement to the P40 parent grant is requesting additional funds to examine baboons as an animal model for accelerated aging, and to establish baseline data for AD and aging-associated biomarkers to increase the utility of this research resource. In Aim 1, we propose using DNA methylation levels to create a baboon-specific DMC in 175 mother- and nursery-reared baboons aged 3-19 years old. We will use this DMC to predict chronological age, and the discrepancy between chronological and epigenetic age will be used to identify individuals that show age acceleration. Additionally, given that nursery-rearing (an early life stressor) is associated with a host of deleterious effects on behavior and physiology, we will investigate the relationship between nursery-rearing and accelerated aging. If this indeed accelerates aging, nursery-reared baboons would serve as an important experimental animal model of early life stress, aging, and the development of AD. In Aim 2, we will establish baseline levels of AD/ADRD biomarkers, as well as determine whether age acceleration in this baboon model is associated with said biomarkers. Multiplexed Luminex biomarkers will include plasma levels of an 18-plex neuroscience panel including AD/ADRD biomarkers such as amyloid and tau proteins, a 10-plex of diabetes biomarkers, neutrophil to lymphocyte ratio (NLR), as well as behavioral markers (i.e., walking speed and motor performance), at two time points in the 175 baboons from Aim 1. We will also examine levels of these biomarkers in cerebrospinal fluid in a subset of 20 geriatric baboons at two time points as well (15 years and older).The proposed project will create a better-defined research resource under the P40 parent grant by 1) creating an experimental model of accelerated aging that can be used to test interventions in controlled settings; and 2) establish baselines of AD/ADRD biomarkers in the baboon sample, thereby increasing characterization of the population and opening avenues for longitudinal AD/ADRD research.