Aging activates escape of the silent X chromosome in the female mouse hippocampus
Women live longer than men and exhibit less cognitive aging. The X chromosome contributes to sex differences, as females harbor an inactive X (Xi) and active X (Xa), in contrast to males with only an Xa. Thus, reactivation of silent Xi genes may contribute to sex differences. We use allele-specific, single-nucleus RNA sequencing to show that aging remodels transcription of the Xi and Xa across hippocampal cell types. Aging preferentially changed gene expression on the X's relative to autosomes. Select genes on the Xi underwent activation, with new escape across cells including in the dentate gyrus, critical to learning and memory. Expression of the Xi escapee <i>Plp1</i>, a myelin component, was increased in the aging hippocampus of female mice and parahippocampus of women. AAV-mediated <i>Plp1</i> elevation in the dentate gyrus of aging male and female mice improved cognition. Understanding how the Xi may confer female advantage could lead to novel targets that counter brain aging and disease in both sexes.
Authors
- Margaret Gadek (ORCID: https://orcid.org/0000-0001-5453-6909)
- Dena B. Dubal (ORCID: https://orcid.org/0000-0001-7504-4372)
- Samira Abdulai-Saiku (ORCID: https://orcid.org/0000-0003-3772-4646)
- Rowan Saloner (ORCID: https://orcid.org/0000-0002-1351-6183)
- Vijay Ramani (ORCID: https://orcid.org/0000-0003-3345-5960)
- Barbara Panning (ORCID: https://orcid.org/0000-0002-8301-1172)
- Francesca Marino (ORCID: https://orcid.org/0000-0002-7899-4282)
- Kaitlin Blackstone Casaletto (ORCID: https://orcid.org/0000-0001-5000-7604)
- Bérénice Anath Benayoun (ORCID: https://orcid.org/0000-0002-7401-4777)
- Luke W. Bonham (ORCID: https://orcid.org/0000-0002-2533-1266)
- Jennifer S. Yokoyama (ORCID: https://orcid.org/0000-0001-7274-2634)
- Cayce K. Shaw (ORCID: https://orcid.org/0000-0001-6636-9810)
- Dan Wang (ORCID: https://orcid.org/0000-0001-9079-2360)
Institutions
- University of Southern California (US)
- Gladstone Institutes (US)
- University of California, San Francisco (US)
- Keck Hospital of USC (US)
- University Memory and Aging Center (US)
- USC Norris Comprehensive Cancer Center (US)
Publication Details
- Journal
- Science Advances
- Published
- 2025-03-05
- DOI
- https://doi.org/10.1126/sciadv.ads8169
- Citations
- 32
- Primary Topic
- Genetics and Neurodevelopmental Disorders
- Type
- article
- Field-Weighted Citation Impact
- 58.15