Single-cell transcriptomic and genomic changes in the ageing human brain

Ailsa M. Jeffries, Tianxiong Yu, Jennifer S. Ziegenfuss, Allie K. Tolles, Christina E. Baer, Cesar Bautista Sotelo, Yerin Kim, Zhiping Weng () and Michael A. Lodato ()
Additional contact information
Ailsa M. Jeffries: University of Massachusetts Chan Medical School
Tianxiong Yu: University of Massachusetts Chan Medical School
Jennifer S. Ziegenfuss: University of Massachusetts Chan Medical School
Allie K. Tolles: University of Massachusetts Chan Medical School
Christina E. Baer: University of Massachusetts Chan Medical School
Cesar Bautista Sotelo: University of Massachusetts Chan Medical School
Yerin Kim: University of Massachusetts Chan Medical School
Zhiping Weng: University of Massachusetts Chan Medical School
Michael A. Lodato: University of Massachusetts Chan Medical School

Nature, 2025, vol. 646, issue 8085, 657-666

Abstract: Abstract Over time, cells in the brain and in the body accumulate damage, which contributes to the ageing process1. In the human brain, the prefrontal cortex undergoes age-related changes that can affect cognitive functioning later in life2. Here, using single-nucleus RNA sequencing (snRNA-seq), single-cell whole-genome sequencing (scWGS) and spatial transcriptomics, we identify gene-expression and genomic changes in the human prefrontal cortex across lifespan, from infancy to centenarian. snRNA-seq identified infant-specific cell clusters enriched for the expression of neurodevelopmental genes, as well as an age-associated common downregulation of cell-essential homeostatic genes that function in ribosomes, transport and metabolism across cell types. Conversely, the expression of neuron-specific genes generally remains stable throughout life. These findings were validated with spatial transcriptomics. scWGS identified two age-associated mutational signatures that correlate with gene transcription and gene repression, respectively, and revealed gene length- and expression-level-dependent rates of somatic mutation in neurons that correlate with the transcriptomic landscape of the aged human brain. Our results provide insight into crucial aspects of human brain development and ageing, and shed light on transcriptomic and genomic dynamics.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-025-09435-8 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:646:y:2025:i:8085:d:10.1038_s41586-025-09435-8

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-025-09435-8

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().