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

## TL;DR

This study identifies key molecular changes in the hippocampus of rhesus macaques during midlife that may influence brain aging and neurodegenerative disease risk.

## Contribution

The study reveals midlife transitions in hippocampal gene expression patterns in rhesus macaques, highlighting age-related molecular changes previously underexplored.

## Key findings

- 2679 differentially expressed genes were identified, showing linear or nonlinear age-related expression patterns.
- Nonlinear gene expression patterns suggest critical transitions around 10 years of age in macaques (~30 in humans).
- Gene expression variance increases significantly in individuals over 20 years of age (~50 in humans).

## Abstract

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.

The online version contains supplementary material available at 10.1007/s11357-025-01834-z.