Doctoral Dissertation Research: Molecular signatures of aging in the primate hippocampus

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Primates are notable for their long, slow life histories and extended lifespans, a trend exaggerated in humans. The effects of this prolonged lifespan can be observed across the body, including the brain. While general patterns of brain aging are conserved among primates, there is clear variation in the pace of brain aging within and between species. In addition, humans are potentially more vulnerable to neurodegenerative diseases associated with the aging process; however, it is not clear what molecular mechanisms enable or shape this variation. This doctoral dissertation project characterizes molecular signatures of aging in the hippocampus of a non-human primate to identify conserved and derived features of primate brain aging and advance our understanding of potential evolved differences in humans that may increase our susceptibility to age-related brain disease. The project broadens the participation of graduate and undergraduate students, including those from underrepresented group in STEM, providing training, mentoring, and research experiences in bioinformatics and genomic analyses. In addition, with life expectancy increasing globally, this project addresses a specific global health concern by improving our understanding of the aging process at the molecular level and by contributing a valuable molecular dataset for future aging-related research.The central hypothesis of this research is that gene regulation shapes hippocampal aging by mediating the interaction between a primate’s environment and biology across its lifespan. Objective 1 characterizes gene expression in the hippocampus of rhesus macaques across the lifespan using existing biosamples. These data are then integrated with previously generated matched DNA methylation data to identify differentially methylated regions that may regulate the expression of age-associated genes in the hippocampus. Objective 2 identifies microRNAs expressed in the hippocampus of rhesus macaques and characterizes their patterns of expression across the lifespan. These data are then integrated with matched gene expression data from Objective 1 to identify candidate miRNA-mRNA pairs and networks. To meet these objectives, matched mRNA and miRNA data are generated and analyzed for hippocampus samples using RNAseq and small RNAseq respectively. Importantly, this dataset includes both males and females and a range of ages.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.