Epigenetic and 3D genome reprogramming during the aging of the human hippocampus
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.
Authors
- Xiangmin Xu (ORCID: https://orcid.org/0000-0002-5828-1533)
- Nathan R. Zemke (ORCID: https://orcid.org/0000-0002-6326-5925)
- Varun Ajith
- Emily Hsu (ORCID: https://orcid.org/0000-0001-5096-0745)
- Joseph R. Ecker (ORCID: https://orcid.org/0000-0001-5799-5895)
- Seo Yeon Lee (ORCID: https://orcid.org/0000-0003-2585-7863)
- Christopher K. Glass (ORCID: https://orcid.org/0000-0003-4344-3592)
- Chumo Chen
- Bing Yang (ORCID: https://orcid.org/0000-0001-6739-2932)
- Liqi Tong (ORCID: https://orcid.org/0000-0001-9470-5885)
- Sainath Mamde
- Jingtian Zhou (ORCID: https://orcid.org/0000-0003-2060-1922)
- Daofeng Li (ORCID: https://orcid.org/0000-0001-7492-3703)
- B. Maximiliano Garduño (ORCID: https://orcid.org/0000-0001-8828-0614)
- Pik Ki Lau
- Hannah S. Indralingam (ORCID: https://orcid.org/0009-0000-1790-109X)
- Ting Wang (ORCID: https://orcid.org/0000-0002-6800-242X)
- Bing Ren
- Keyi Dong
- Weronika M. Bartosik
- Carl W. Cotman
- Nicole Berchtold
- Chanrung Seng
- Yasmine Tani
- Amanda Yang
- Qiurui Zeng
Institutions
- James S. McDonnell Foundation (US)
- University of Southern California (US)
- Salk Institute for Biological Studies (US)
- Howard Hughes Medical Institute (US)
- University of California, Irvine (US)
- Washington University in St. Louis (US)
- University of California San Diego (US)
- Alpine Immune Sciences (United States) (US)
- USC Norris Comprehensive Cancer Center (US)
- Palo Alto Institute (US)
- New York Genome Center (US)
- Arc Research Institute
- Columbia University (US)
Publication Details
- Journal
- Science
- Published
- 2026-07-23
- DOI
- https://doi.org/10.1126/science.adt8307
- Citations
- 7
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 15.88
Funders
- National Institutes of Health
- Common Fund