Patterns of transcriptomic aging in the hippocampus of rhesus macaques highlight midlife transitions

Patterns of brain aging are generally conserved among primates; however, there is marked variation in the observed rate among individuals, species, and brain regions. The hippocampus is a region particularly susceptible to the aging process. To better understand how the hippocampus changes over the lifespan, we measured gene expression in 96 banked hippocampus samples from adult male and female rhesus macaques aged 3-35 years old. Importantly, our dataset included representation across adulthood allowing us to characterize age-related patterns in gene expression during midlife, a period often underrepresented in studies of aging. We used autoregressive integrated moving average models to examine age-associated changes in gene expression to identify 2679 differentially expressed genes (FDR < 0.05) that fit four broad patterns of expression: linearly upregulated or downregulated across age, and two clusters with nonlinear patterns. Importantly, the nonlinear clusters highlight transitions in expression trajectories centered around ~ 10 years of age (~ 30 years of age in humans) indicating an important period that may have a critical impact on hippocampal aging. Changes in gene expression variance across age found that genes in individuals > 20 years of age (> 50 years of age in humans) have greater variance in expression than individuals aged 10-20 years (FDR < 0.05). Collectively, our results highlight molecular changes occurring during midlife which may shape brain aging in longer lived primates and may offer insight into increased susceptibility to neurodegenerative disease in humans.