Atlas of the aging mouse brain reveals white matter as vulnerable foci

Oliver Hahn; Aulden G Foltz; Micaiah Atkins; Blen Kedir; Patricia Moran-Losada; Ian H Guldner; Christy Munson; Fabian Kern; Róbert Pálovics; Nannan Lu; Hui Zhang; Achint Kaur; Jacob Hull; John R Huguenard; Sebastian Grönke; Benoit Lehallier; Linda Partridge; Andreas Keller; Tony Wyss-Coray

doi:10.1016/j.cell.2023.07.027

Atlas of the aging mouse brain reveals white matter as vulnerable foci

Cell. 2023 Sep 14;186(19):4117-4133.e22. doi: 10.1016/j.cell.2023.07.027. Epub 2023 Aug 16.

Authors

Oliver Hahn¹, Aulden G Foltz¹, Micaiah Atkins¹, Blen Kedir¹, Patricia Moran-Losada¹, Ian H Guldner¹, Christy Munson², Fabian Kern³, Róbert Pálovics¹, Nannan Lu¹, Hui Zhang¹, Achint Kaur¹, Jacob Hull¹, John R Huguenard¹, Sebastian Grönke⁴, Benoit Lehallier⁵, Linda Partridge⁶, Andreas Keller³, Tony Wyss-Coray⁷

Affiliations

¹ Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA; Wu Tsai Neurosciences Institute, Stanford University School of Medicine, Stanford, CA, USA.
² Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA; Wu Tsai Neurosciences Institute, Stanford University School of Medicine, Stanford, CA, USA; Vilcek Institute of Graduate Biomedical Sciences, NYU Langone Health, New York City, NY, USA.
³ Clinical Bioinformatics, Saarland University, Saarbrücken, Germany; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz-Centre for Infection Research (HZI), Saarbrücken, Germany.
⁴ Max Planck Institute for Biology of Ageing, Cologne, Germany.
⁵ Alkahest Inc., San Carlos, CA, USA.
⁶ Max Planck Institute for Biology of Ageing, Cologne, Germany; Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, University College London, London, UK.
⁷ Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA; Wu Tsai Neurosciences Institute, Stanford University School of Medicine, Stanford, CA, USA; Paul F. Glenn Center for the Biology of Aging, Stanford University, Stanford, CA, USA; Stanford University, The Phil and Penny Knight Initiative for Brain Resilience, Stanford, CA, USA. Electronic address: [email protected].

Abstract

Aging is the key risk factor for cognitive decline, yet the molecular changes underlying brain aging remain poorly understood. Here, we conducted spatiotemporal RNA sequencing of the mouse brain, profiling 1,076 samples from 15 regions across 7 ages and 2 rejuvenation interventions. Our analysis identified a brain-wide gene signature of aging in glial cells, which exhibited spatially defined changes in magnitude. By integrating spatial and single-nucleus transcriptomics, we found that glial aging was particularly accelerated in white matter compared with cortical regions, whereas specialized neuronal populations showed region-specific expression changes. Rejuvenation interventions, including young plasma injection and dietary restriction, exhibited distinct effects on gene expression in specific brain regions. Furthermore, we discovered differential gene expression patterns associated with three human neurodegenerative diseases, highlighting the importance of regional aging as a potential modulator of disease. Our findings identify molecular foci of brain aging, providing a foundation to target age-related cognitive decline.

Keywords: aging; dietary restriction; neurodegeneration; neurogenomics; neuroscience; single-cell biology.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aging*
Animals
Brain / pathology
Cognitive Dysfunction* / genetics
Gene Expression Profiling
Humans
Mice
Single-Cell Gene Expression Analysis
Solitary Nucleus
White Matter* / pathology

Grants and funding

R01 AG072255/AG/NIA NIH HHS/United States