Molecular and genetic insights into human ovarian aging from single-nuclei multi-omics analyses
The ovary is the first organ to age in the human body, affecting both fertility and overall health. However, the biological mechanisms underlying human ovarian aging remain poorly understood. Here we present a comprehensive single-nuclei multi-omics atlas of four young (ages 23-29 years) and four reproductively aged (ages 49-54 years) human ovaries. Our analyses reveal coordinated changes in transcriptomes and chromatin accessibilities across cell types in the ovary during aging, notably mTOR signaling being a prominent ovary-specific aging pathway. Cell-type-specific regulatory networks reveal enhanced activity of the transcription factor CEBPD across cell types in the aged ovary. Integration of our multi-omics data with genetic variants associated with age at natural menopause demonstrates a global impact of functional variants on gene regulatory networks across ovarian cell types. We nominate functional non-coding regulatory variants, their target genes and ovarian cell types and regulatory mechanisms. This atlas provides a valuable resource for understanding the cellular, molecular and genetic basis of human ovarian aging.
Authors
- Michael G. Rosenfeld (ORCID: https://orcid.org/0000-0002-1572-156X)
- Judith Campisi (ORCID: https://orcid.org/0000-0001-6858-9462)
- Rogerio A. Løbo (ORCID: https://orcid.org/0000-0002-1472-8313)
- Jan Vijg (ORCID: https://orcid.org/0000-0002-8457-9595)
- Adam D. Hudgins (ORCID: https://orcid.org/0000-0002-2737-6839)
- Chen Jin (ORCID: https://orcid.org/0000-0003-4075-4723)
- Jan H.J. Hoeijmakers (ORCID: https://orcid.org/0000-0003-3526-7795)
- Xizhe Wang
- Zev Williams (ORCID: https://orcid.org/0000-0001-8563-3250)
- Mingzhuo Pei
- Melody Devos (ORCID: https://orcid.org/0000-0002-5601-9769)
- Daniela Contreras (ORCID: https://orcid.org/0000-0001-7907-5870)
- Yousin Suh (ORCID: https://orcid.org/0000-0002-6014-3084)
- Jiping Yang (ORCID: https://orcid.org/0000-0001-6332-8693)
- Seung-Soo Kim
- Qinghua Guo (ORCID: https://orcid.org/0000-0002-4469-5997)
- Marco Conti (ORCID: https://orcid.org/0000-0003-4755-9146)
- Amir Gamliel
Institutions
- Albert Einstein College of Medicine (US)
- Buck Institute for Research on Aging (US)
- Howard Hughes Medical Institute (US)
- Lawrence Berkeley National Laboratory (US)
- University of California, San Francisco (US)
- Columbia University Irving Medical Center (US)
- Erasmus MC (NL)
- University of California San Diego (US)
- Reproductive Science Center (US)
- Oncode Institute (NL)
- Princess Máxima Center (NL)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
- Broad Center (US)
- University of San Francisco (US)
Publication Details
- Journal
- Nature Aging
- Published
- 2024-11-22
- DOI
- https://doi.org/10.1038/s43587-024-00762-5
- Citations
- 53
- Primary Topic
- Genetics, Aging, and Longevity in Model Organisms
- Type
- article
- Field-Weighted Citation Impact
- 12.07
Funders
- Simons Foundation
- National Institutes of Health