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Single-cell atlas of the mouse ovary reveals molecular drivers of aging and senescence during the estropausal transition.

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Title: Single-cell atlas of the mouse ovary reveals molecular drivers of aging and senescence during the estropausal transition.
Authors: Wang X; Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, NY 10032., Yang J; Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, NY 10032., Jin C; Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, NY 10032., Wang X; Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, NY 10032., Contreras D; Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, NY 10032., Devos M; Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, NY 10032., Kane MM; Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032., Rosenfeld MG; Department of Medicine, University of California San Diego, La Jolla, CA 92093., Suh Y; Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, NY 10032.; Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032.
Source: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2026 Jul 28; Vol. 123 (30), pp. e2600323123. Date of Electronic Publication: 2026 Jul 21.
Publication Type: Journal Article
Language: English
Journal Info: Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
Imprint Name(s): Original Publication: Washington, DC : National Academy of Sciences
MeSH Terms: Ovary*/metabolism , Ovary*/cytology , Ovary*/physiology , Cellular Senescence*/genetics , Cellular Senescence*/physiology , Aging*/genetics , Aging*/physiology , Aging*/metabolism , Estrous Cycle*/physiology, Granulosa Cells/metabolism ; Animals ; Female ; Mice ; Single-Cell Analysis ; Transcriptome ; Single-Cell Gene Expression Analysis
Abstract: Reproductive aging in mice leads to estropause, characterized by estrous cycle irregularity and eventual cessation, yet its underlying mechanism remains unclear. Here, we present a comprehensive single-cell atlas of mouse ovaries across precisely defined reproductive stages-from young (regular cycling) through the estropausal transition (regular vs. irregular cycling) to post-estropause (acyclic)-and of ovary-specific senescent cells defined by high senescence-associated β-galactosidase activity. We mapped transcriptomic dynamics of ovarian aging and characterized the molecular features of ovarian senescent cells. Our analyses revealed that during the estropausal transition, irregularly cycling ovaries exhibited accelerated aging and cellular senescence features compared with regularly cycling counterparts, including increased transcriptional noise, altered conserved aging pathways such as oxidative phosphorylation and proteostasis, hormone dysregulation in granulosa cells, and elevated expression of the senescence marker Cdkn1a and senescence-associated secretory phenotype factors. This atlas delineates the cellular and molecular hallmarks of mouse ovarian aging and ovary-specific senescent cells, providing a resource for understanding the mechanisms underlying the estropausal transition.
Competing Interests: Competing interests statement:The authors declare no competing interest.
Grant Information: AG069750 HHS | NIH (NIH); DK127778 AG057433 AG061521 HL150521 AG055501 AG057341 AG057433 AG057706 AG057909 AG017242 HHS | NIH (NIH); GCRLE-1320 Global Consortium for Reproductive Longevity; N/A Simons Foundation (SF); PD25221 Glenn Foundation for Medical Research (GFMR)
Contributed Indexing: Keywords: aging; cellular senescence; estropausal transition; ovary; single-cell RNA-seq
Entry Date(s): Date Created: 20260721 Date Completed: 20260721 Latest Revision: 20260731
Update Code: 20260731
PubMed Central ID: PMC13416851
DOI: 10.1073/pnas.2600323123
PMID: 42479833
Database: MEDLINE
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  Data: Single-cell atlas of the mouse ovary reveals molecular drivers of aging and senescence during the estropausal transition.
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  Data: <searchLink fieldCode="AU" term="%22Wang+X%22">Wang X</searchLink>; Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, NY 10032.<br /><searchLink fieldCode="AU" term="%22Yang+J%22">Yang J</searchLink>; Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, NY 10032.<br /><searchLink fieldCode="AU" term="%22Jin+C%22">Jin C</searchLink>; Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, NY 10032.<br /><searchLink fieldCode="AU" term="%22Wang+X%22">Wang X</searchLink>; Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, NY 10032.<br /><searchLink fieldCode="AU" term="%22Contreras+D%22">Contreras D</searchLink>; Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, NY 10032.<br /><searchLink fieldCode="AU" term="%22Devos+M%22">Devos M</searchLink>; Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, NY 10032.<br /><searchLink fieldCode="AU" term="%22Kane+MM%22">Kane MM</searchLink>; Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032.<br /><searchLink fieldCode="AU" term="%22Rosenfeld+MG%22">Rosenfeld MG</searchLink>; Department of Medicine, University of California San Diego, La Jolla, CA 92093.<br /><searchLink fieldCode="AU" term="%22Suh+Y%22">Suh Y</searchLink>; Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, NY 10032.; Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032.
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  Data: <searchLink fieldCode="JN" term="%227505876%22">Proceedings of the National Academy of Sciences of the United States of America</searchLink> [Proc Natl Acad Sci U S A] 2026 Jul 28; Vol. 123 (30), pp. e2600323123. <i>Date of Electronic Publication: </i>2026 Jul 21.
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  Data: <i>Publisher: </i><searchLink fieldCode="PB" term="%22National+Academy+of+Sciences%22">National Academy of Sciences </searchLink><i>Country of Publication: </i>United States <i>NLM ID: </i>7505876 <i>Publication Model: </i>Print-Electronic <i>Cited Medium: </i>Internet <i>ISSN: </i>1091-6490 (Electronic) <i>Linking ISSN: </i><searchLink fieldCode="IS" term="%2200278424%22">00278424 </searchLink><i>NLM ISO Abbreviation: </i>Proc Natl Acad Sci U S A <i>Subsets: </i>MEDLINE
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  Data: <i>Original Publication</i>: Washington, DC : National Academy of Sciences
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  Data: <searchLink fieldCode="MM" term="%22Ovary%22">Ovary*</searchLink>/<searchLink fieldCode="MM" term="%22Ovary+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Ovary%22">Ovary*</searchLink>/<searchLink fieldCode="MM" term="%22Ovary+cytology%22">cytology</searchLink> <br /><searchLink fieldCode="MM" term="%22Ovary%22">Ovary*</searchLink>/<searchLink fieldCode="MM" term="%22Ovary+physiology%22">physiology</searchLink> <br /><searchLink fieldCode="MM" term="%22Cellular+Senescence%22">Cellular Senescence*</searchLink>/<searchLink fieldCode="MM" term="%22Cellular+Senescence+genetics%22">genetics</searchLink> <br /><searchLink fieldCode="MM" term="%22Cellular+Senescence%22">Cellular Senescence*</searchLink>/<searchLink fieldCode="MM" term="%22Cellular+Senescence+physiology%22">physiology</searchLink> <br /><searchLink fieldCode="MM" term="%22Aging%22">Aging*</searchLink>/<searchLink fieldCode="MM" term="%22Aging+genetics%22">genetics</searchLink> <br /><searchLink fieldCode="MM" term="%22Aging%22">Aging*</searchLink>/<searchLink fieldCode="MM" term="%22Aging+physiology%22">physiology</searchLink> <br /><searchLink fieldCode="MM" term="%22Aging%22">Aging*</searchLink>/<searchLink fieldCode="MM" term="%22Aging+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Estrous+Cycle%22">Estrous Cycle*</searchLink>/<searchLink fieldCode="MM" term="%22Estrous+Cycle+physiology%22">physiology</searchLink><br /><searchLink fieldCode="MH" term="%22Granulosa+Cells%22">Granulosa Cells</searchLink>/<searchLink fieldCode="MH" term="%22Granulosa+Cells+metabolism%22">metabolism</searchLink> ; <searchLink fieldCode="MH" term="%22Animals%22">Animals</searchLink> ; <searchLink fieldCode="MH" term="%22Female%22">Female</searchLink> ; <searchLink fieldCode="MH" term="%22Mice%22">Mice</searchLink> ; <searchLink fieldCode="MH" term="%22Single-Cell+Analysis%22">Single-Cell Analysis</searchLink> ; <searchLink fieldCode="MH" term="%22Transcriptome%22">Transcriptome</searchLink> ; <searchLink fieldCode="MH" term="%22Single-Cell+Gene+Expression+Analysis%22">Single-Cell Gene Expression Analysis</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Reproductive aging in mice leads to estropause, characterized by estrous cycle irregularity and eventual cessation, yet its underlying mechanism remains unclear. Here, we present a comprehensive single-cell atlas of mouse ovaries across precisely defined reproductive stages-from young (regular cycling) through the estropausal transition (regular vs. irregular cycling) to post-estropause (acyclic)-and of ovary-specific senescent cells defined by high senescence-associated β-galactosidase activity. We mapped transcriptomic dynamics of ovarian aging and characterized the molecular features of ovarian senescent cells. Our analyses revealed that during the estropausal transition, irregularly cycling ovaries exhibited accelerated aging and cellular senescence features compared with regularly cycling counterparts, including increased transcriptional noise, altered conserved aging pathways such as oxidative phosphorylation and proteostasis, hormone dysregulation in granulosa cells, and elevated expression of the senescence marker Cdkn1a and senescence-associated secretory phenotype factors. This atlas delineates the cellular and molecular hallmarks of mouse ovarian aging and ovary-specific senescent cells, providing a resource for understanding the mechanisms underlying the estropausal transition.
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  Data: Competing interests statement:The authors declare no competing interest.
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  Data: AG069750 HHS | NIH (NIH); DK127778 AG057433 AG061521 HL150521 AG055501 AG057341 AG057433 AG057706 AG057909 AG017242 HHS | NIH (NIH); GCRLE-1320 Global Consortium for Reproductive Longevity; N/A Simons Foundation (SF); PD25221 Glenn Foundation for Medical Research (GFMR)
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  Data: <i>Keywords: </i>aging; cellular senescence; estropausal transition; ovary; single-cell RNA-seq
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  Data: <i>Date Created: </i>20260721 <i>Date Completed: </i>20260721 <i>Latest Revision: </i>20260731
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  Data: 10.1073/pnas.2600323123
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        Text: English
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      – SubjectFull: Granulosa Cells metabolism
        Type: general
      – SubjectFull: Animals
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      – SubjectFull: Female
        Type: general
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      – SubjectFull: Ovary metabolism
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      – SubjectFull: Ovary physiology
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      – SubjectFull: Cellular Senescence genetics
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