Molecular Signatures of Aging in the Hippocampus of Rhesus Macaques

Understanding why humans are uniquely susceptible to neurodegenerative diseases (e.g., Alzheimer's disease) requires insight into how the molecular architecture of the aging brain is organized and regulated – and how that organization may differ across primates with different levels of vulnerability to neurodegenerative diseases. This dissertation investigates molecular signatures of aging in the hippocampus of rhesus macaques (Macaca mulatta), a long-lived nonhuman primate that shares key features of brain organization, life history, physiology and genetic similarity with humans, making it a powerful translational model for studying primate brain aging. Using a multi-omic approach integrating bulk RNA-sequencing, reduced representation bisulfite sequencing, and small RNA-sequencing from matched hippocampal tissue samples spanning the full adult lifespan (~3-35 years of age), I characterize how gene expression, DNA methylation, and microRNA expression differ and interact across the lifespan in a brain region central to learning, memory, and neurodegenerative vulnerability.Across all three molecular layers, I find evidence for several hallmarks of aging, including epigenetic alterations, inflammatory signaling, disrupted intercellular communication, and pathways associated with mitochondrial dysfunction. Critically, molecular aging in the macaque hippocampus does not always follow strictly linear trajectories. In fact, all three omic datasets reveal nonlinear molecular trajectories with a recurring midlife transition centered around ~10 years of age in macaques – a period that corresponds roughly to ~30 years of age in humans. This convergence across independent molecular datasets suggests that midlife may represent a critical window of regulatory reorganization in the primate brain, one that could shape later-life vulnerability to cognitive decline and neurodegeneration. By integrating data across molecular layers, I identify candidate regulatory networks – linking DNA methylation at cis-regulatory elements to age-associated gene expression changes, and potential miRNA-mediated post-transcriptional control to transcriptional remodeling – that may play important roles in shaping hippocampal aging. Several of these candidate regulatory relationships implicate genes and pathways with direct relevance to human neurodegenerative disease. From a biological anthropology perspective, characterizing the molecular landscape of normal brain aging in a nonhuman primate provides an essential comparative baseline for understanding what is shared and what is derived in human brain aging. The regulatory processes identified in this dissertation – shaped across the lifespan by both biology and environment – highlight important genes and pathways in primate aging that may show divergent regulation in humans, potentially underlying our increased vulnerability to neurodegenerative disease. This dissertation includes supplemental files in the form of tables. This dissertation includes previously published co-authored material.