Epigenetic and 3D genome reprogramming during the aging of the human hippocampus

Science 2026 Open access

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Authors: Nathan R. Zemke, Seo Yeon 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
+14 more 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
DOI: 10.1126/science.adt8307
Cited by: 7
References: 87

Abstract

Age-related cognitive decline is associated with altered physiology of the hippocampus. While changes in gene expression have been observed in aging brain, the regulatory mechanisms underlying these changes remain underexplored. We generated single-nucleus gene expression, chromatin accessibility, DNA methylation, and 3D genome data from 40 human hippocampal tissues spanning adult lifespan. We observed a striking loss of astrocytes, OPC, and endothelial cells during aging, including astrocytes that play a role in regulating synapses. Microglia undergo a dramatic switch from a homeostatic state to a primed inflammatory state through DNA methylome and 3D genome reprogramming. Aged cells experience erosion of their 3D genome architecture. Our study identifies age-associated changes in cell types/states and gene regulatory features that provide insight into cognitive decline during human aging.

Fields of Study & Subjects

Neuroinflammation and Neurodegeneration Mechanisms Single-cell and spatial transcriptomics Epigenetics and DNA Methylation

Publication details

Journal / source
Science
Publisher
American Association for the Advancement of Science (AAAS)
Volume
393
Issue
6809
Pages
eadt8307–eadt8307
Publication date
23 July 2026
Language
EN