Molecular and genetic insights into human ovarian aging from single-nuclei multi-omics analyses

Chen Jin; Xizhe Wang; Jiping Yang; Seungsoo Kim; Adam D. Hudgins; Amir Gamliel; Mingzhuo Pei; Daniela Contreras; Melody Devos; Qinghua Guo; Jan Vijg; Marco Conti; Jan Hoeijmakers; Judith Campisi; Rogerio Lobo; Zev Williams; Michael G. Rosenfeld; Yousin Suh

doi:10.1038/s43587-024-00762-5

Molecular and genetic insights into human ovarian aging from single-nuclei multi-omics analyses

Chen Jin^*, Xizhe Wang, Jiping Yang, Seungsoo Kim, Adam D. Hudgins, Amir Gamliel, Mingzhuo Pei, Daniela Contreras, Melody Devos, Qinghua Guo, Jan Vijg, Marco Conti, Jan Hoeijmakers, Judith Campisi, Rogerio Lobo, Zev Williams, Michael G. Rosenfeld, Yousin Suh^*

^*Corresponding author for this work

Molecular Genetics

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Abstract

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.

Original language	English
Article number	e13304
Pages (from-to)	275-290
Number of pages	16
Journal	Nature Aging
Volume	5
Issue number	2
DOIs	https://doi.org/10.1038/s43587-024-00762-5
Publication status	Published - Feb 2025

Bibliographical note

Publisher Copyright: © The Author(s) 2024.

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s43587-024-00762-5Final published version, 20.1 MBLicence: CC BY-NC-ND

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Jin, C., Wang, X., Yang, J., Kim, S., Hudgins, A. D., Gamliel, A., Pei, M., Contreras, D., Devos, M., Guo, Q., Vijg, J., Conti, M., Hoeijmakers, J., Campisi, J., Lobo, R., Williams, Z., Rosenfeld, M. G., & Suh, Y. (2025). Molecular and genetic insights into human ovarian aging from single-nuclei multi-omics analyses. Nature Aging, 5(2), 275-290. Article e13304. https://doi.org/10.1038/s43587-024-00762-5

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title = "Molecular and genetic insights into human ovarian aging from single-nuclei multi-omics analyses",

abstract = "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.",

author = "Chen Jin and Xizhe Wang and Jiping Yang and Seungsoo Kim and Hudgins, \{Adam D.\} and Amir Gamliel and Mingzhuo Pei and Daniela Contreras and Melody Devos and Qinghua Guo and Jan Vijg and Marco Conti and Jan Hoeijmakers and Judith Campisi and Rogerio Lobo and Zev Williams and Rosenfeld, \{Michael G.\} and Yousin Suh",

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year = "2025",

month = feb,

doi = "10.1038/s43587-024-00762-5",

language = "English",

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Jin, C, Wang, X, Yang, J, Kim, S, Hudgins, AD, Gamliel, A, Pei, M, Contreras, D, Devos, M, Guo, Q, Vijg, J, Conti, M, Hoeijmakers, J, Campisi, J, Lobo, R, Williams, Z, Rosenfeld, MG & Suh, Y 2025, 'Molecular and genetic insights into human ovarian aging from single-nuclei multi-omics analyses', Nature Aging, vol. 5, no. 2, e13304, pp. 275-290. https://doi.org/10.1038/s43587-024-00762-5

TY - JOUR

T1 - Molecular and genetic insights into human ovarian aging from single-nuclei multi-omics analyses

AU - Jin, Chen

AU - Wang, Xizhe

AU - Yang, Jiping

AU - Kim, Seungsoo

AU - Hudgins, Adam D.

AU - Gamliel, Amir

AU - Pei, Mingzhuo

AU - Contreras, Daniela

AU - Devos, Melody

AU - Guo, Qinghua

AU - Vijg, Jan

AU - Conti, Marco

AU - Hoeijmakers, Jan

AU - Campisi, Judith

AU - Lobo, Rogerio

AU - Williams, Zev

AU - Rosenfeld, Michael G.

AU - Suh, Yousin

PY - 2025/2

Y1 - 2025/2

N2 - 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.

AB - 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.

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JF - Nature Aging

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ER -

Molecular and genetic insights into human ovarian aging from single-nuclei multi-omics analyses

Abstract

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