The DOI matches its Crossref record; 92 of the 93 references it cites were found in a registry or an index.
Cellular hallmarks of aging emerge in the ovary prior to primordial follicle depletion
Open accessAbstract
Decline in ovarian reserve with advancing age is associated with reduced fertility and the emergence of metabolic disturbances, osteoporosis, and neurodegeneration. Recent studies have provided insight into connections between ovarian insufficiency and systemic aging, although the basic mechanisms that promote ovarian reserve depletion remain unknown. Here, we sought to determine if chronological age is linked to changes in ovarian cellular senescence, transcriptomic, and epigenetic mechanisms in a mouse model. Histological assessments and transcriptional analyses revealed the accumulation of lipofuscin aggresomes and senescence-related transcripts (Cdkn1a, Cdkn2a, Pai-1 and Hmgb1) significantly increased with advancing age. Transcriptomic profiling and pathway analyses following RNA sequencing, revealed an upregulation of genes related to pro-inflammatory stress and cell-cycle inhibition, whereas genes involved in cell-cycle progression were downregulated; which could be indicative of senescent cell accumulation. The emergence of these senescence-related markers preceded the dramatic decline in primordial follicle reserve observed. Whole Genome Oxidative Bisulfite Sequencing (WGoxBS) found no genome-wide or genomic context-specific DNA methylation and hydroxymethylation changes with advancing age. These findings suggest that cellular senescence may contribute to ovarian aging, and thus, declines in ovarian follicular reserve. Cell-type-specific analyses across the reproductive lifespan are needed to fully elucidate the mechanisms that promote ovarian insufficiency.
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“The secretion of SASP factors such as Ccl8 (ref. 239), CCL5 (ref. 241) and the pro-inflammatory related gene Crlf1 (ref. 239) also increases with age.”
From SenNet recommendations for detecting senescent cells in different tissues (2024) · cites this paper as [239]
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“In ovaries from mice of advanced reproductive age, cells classified as senescent are characterized by increased expression of Cdkn2a (refs. 238–240), Cdkn1a, Serpine1 and Hmgb1 (ref. 239).”
From SenNet recommendations for detecting senescent cells in different tissues (2024) · cites this paper as [239]
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“Additionally, these cells exhibit increased lysosomal content, as indicated by accumulation of lipofuscin aggregates (known as ‘aggresomes’)239 and by SA-β-gal staining in the stromal compartment241.”
From SenNet recommendations for detecting senescent cells in different tissues (2024) · cites this paper as [239]
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SenNet recommendations for detecting senescent cells in different tissues
Suryadevara, V., Hudgins, A. D., Rajesh, A., Pappalardo, A., Karpova, A., Dey, A. K., Hertzel, A., Agudelo, A., Rocha, A., Soygur, B., et al. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00738-8 · Cited by 408
“Additionally, these cells exhibit increased lysosomal content, as indicated by accumulation of lipofuscin aggregates (known as ‘aggresomes’) 239 and by SA-β-gal staining in the stromal compartment 241 Apart from physiological ageing, treatments that accelerate reproductive ageing through genotoxic…”
The role of oxidative stress in ovarian aging: a review
Yan, F., Zhao, Q., Li, Y., Zheng, Z., Kong, X., Shu, C., Liu, Y., & Shi, Y. (2022) · Journal of Ovarian Research · doi:10.1186/s13048-022-01032-x · Cited by 324
A single-cell atlas of the aging mouse ovary
Isola, J. V. V., Ocañas, S. R., Hubbart, C. R., Ko, S.-H., Mondal, S. A., Hense, J. D., Carter, H. N. C., Schneider, A., Kovats, S., Alberola‐Ila, J., et al. (2024) · Nature Aging · doi:10.1038/s43587-023-00552-5 · Cited by 204
Self-citationSpatiotemporal transcriptomic changes of human ovarian aging and the regulatory role of FOXP1
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Reproductive Ageing: Inflammation, immune cells, and cellular senescence in the aging ovary
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Metadata
- Authors
- Ansere, V. A., Ali-Mondal, S., Sathiaseelan, R., Garcia, D. N., Isola, J. V. V., Henseb, J. D., Saccon, T. D., Ocañas, S. R., Tooley, K. B., Stout, M. B., Schneider, A., & Freeman, W. M.
- Affiliations
- University of Oklahoma Health Sciences Center (US)
- Universidade Federal de Pelotas (BR)
- Oklahoma Medical Research Foundation (US)
- Corresponding author
- Freeman, Willard M.
- ORCID
- Venue
- Mechanisms of Ageing and Development
- Publisher
- Elsevier BV
- Published
- 2021-03
- Volume
- 194
- Pages
- 111425
- ISSN
- 0047-6374 (ISSN-L)
- PMC
- PMC8279026
- OpenAlex
- W3117460981
- Cited by
- 101
- References
- 93
- Citations by year
- 2026: 31 · 2025: 22 · 2024: 23 · 2023: 10 · 2022: 12 · 2021: 3
- FWCI
- 4.68
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Mechanisms of Ageing and Development (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Foundation for Aging Research
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- National Institute on Aging
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Reproductive Biology and Fertility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- ovarian aging, cellular senescence, ovarian reserve, primordial follicle depletion, DNA methylation, hydroxymethylation, epigenetics, transcriptomics, oxidative bisulfite sequencing, p21, CDKN2A, plasminogen activator inhibitor-1, HMGB1, inflammation, cell cycle inhibition, mouse model
- MeSH terms
- Age Factors, Aging, Animals, Female, Ovarian Follicle, Mice, Inbred C57BL, Ovary, Cytokines, Primary Ovarian Insufficiency, Cellular Senescence, Cell Cycle Proteins, Inflammation Mediators, DNA Methylation, Gene Expression Profiling, Epigenesis, Genetic, Mice, Transcriptome, Ovarian Reserve
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