FoxM1 repression during human aging leads to mitotic decline and aneuploidy-driven full senescence
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Abstract
Aneuploidy, an abnormal chromosome number, has been linked to aging and age-associated diseases, but the underlying molecular mechanisms remain unknown. Here we show, through direct live-cell imaging of young, middle-aged, and old-aged primary human dermal fibroblasts, that aneuploidy increases with aging due to general dysfunction of the mitotic machinery. Increased chromosome mis-segregation in elderly mitotic cells correlates with an early senescence-associated secretory phenotype (SASP) and repression of Forkhead box M1 (FoxM1), the transcription factor that drives G2/M gene expression. FoxM1 induction in elderly and Hutchison–Gilford progeria syndrome fibroblasts prevents aneuploidy and, importantly, ameliorates cellular aging phenotypes. Moreover, we show that senescent fibroblasts isolated from elderly donors’ cultures are often aneuploid, and that aneuploidy is a key trigger into full senescence phenotypes. Based on this feedback loop between cellular aging and aneuploidy, we propose modulation of mitotic efficiency through FoxM1 as a potential strategy against aging and progeria syndromes.
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This mitotic fidelity loss with age generates daughter cells with aneuploidy and micronuclei that ultimately lead to permanent cell cycle arrest in G1 and full senescence phenotypes.
“This mitotic fidelity loss with age generates daughter cells with aneuploidy and micronuclei that ultimately lead to permanent cell cycle arrest in G1 and full senescence phenotypes [65].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [65]
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References 84 · Cited by 131
- Authors
- Macedo, J. C., Vaz, S., Bakker, B., Ribeiro, R., Bakker, P. L., Escandell, J. M., Ferreira, M. G., Medema, R., Foijer, F., & Logarinho, E.
- Affiliations
- Universidade do Porto (PT)
- University Medical Center Groningen (NL)
- Institut de Recherche sur le Cancer et le Vieillissement de Nice (FR)
- The Netherlands Cancer Institute (NL)
- Corresponding author
- Logarinho, Elsa
- ORCID
- Venue
- Nature Communications
- Published
- 2018-07-19
- Volume
- 9
- Issue
- 1
- Pages
- 2834-2834
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6053425
- OpenAlex
- W2883525804
- Cited by
- 131
- References
- 84
- Citations by year
- 2026: 10 · 2025: 19 · 2024: 13 · 2023: 17 · 2022: 21 · 2021: 22 · 2020: 14 · 2019: 14 · 2018: 1
- FWCI
- 8.74
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
- Funders
- Ministério da Ciência, Tecnologia e Ensino Superior (NORTE 2020, PTDC/BEX-BCM/2090/2014, POCI-01-0145-FEDER-007274, POCI-01-0145, IF/00916/2014)
- Fundação para a Ciência e a Tecnologia (Norte-01-0145-FEDER- 000029, 01-0145, COMPETE, POCI-01-0145, POCI- 01-0145-FEDER-007274, PTDC/BEX-BCM/2090/2014, PORTUGAL 2020, POCI-01-0145-FEDER-, COMPETE_2020, NORTE2020, POCI-01-, IF/00916/2014, SFRH/BD/74002/2010, NORTE-07-0124-FEDER-000003, NORTE-01-0145)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- FOXM1, cellular aging, aneuploidy, chromosome missegregation, senescence-associated secretory phenotype, dermal fibroblasts, Hutchinson-Gilford progeria syndrome, age-related diseases
- MeSH terms
- Forkhead Box Protein M1, Adolescent, Adult, Aged, Aged, 80 and over, Aging, Aneuploidy, Child, Child, Preschool, Fibroblasts, Humans, Infant, Male, Middle Aged, Mitosis, Progeria, Cellular Senescence, Gene Expression Regulation, Developmental, White People, G2 Phase Cell Cycle Checkpoints, Primary Cell Culture
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