Epigenetic and 3D genome reprogramming during the aging of the human hippocampus
- Nathan R. Zemke
- Seoyeon Lee
- Sainath Mamde
- Bing Yang
- Nicole Berchtold
- B. Maximiliano Garduño
- Hannah S. Indralingam
- Weronika M. Bartosik
- Pik Ki Lau
- Keyi Dong
- Emily Hsu
- Amanda Yang
- Yasmine Tani
- Chumo Chen
- Qiurui Zeng
- Varun Ajith
- Liqi Tong
- Chanrung Seng
- Daofeng Li
- Ting Wang
- Jingtian Zhou
- Joseph R. Ecker
- Christopher K. Glass
- Carl W. Cotman
- Xiangmin Xu
- Bing Ren
2026-07-23
Changes in gene expression have been observed in the aging human brain, but our understanding of the underlying regulatory mechanisms remains limited. To unravel these complexities, we analyzed single-nucleus gene expression, chromatin accessibility, DNA methylation, and three-dimensional (3D) chromatin architecture from human hippocampal tissues spanning the adult lifespan. We identified both linear and nonlinear dynamic gene regulatory programs during aging. Between the ages of 50 to 75, embryonic yolk sac–derived microglia were depleted and replaced by cells resembling peripheral blood monocyte–derived microglia. Hippocampal astrocytes decreased substantially with age, including those regulating synaptic transmission. Across cell types, 3D genome architecture underwent global erosion. Our analysis provides insights for how altered gene regulatory programs promote cell type–specific aging phenotypes in the human brain.