Document details
FoxM1 repression during human aging leads to mitotic decline and aneuploidy-driven full senescence(Article)(Open Access)
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- aAging and Aneuploidy Laboratory, IBMC, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, 4200-135, Portugal
- bi3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, 4200-135, Portugal
- cEuropean Research Institute for the Biology of Aging, University of Groningen, University Medical Center Groningen, Groningen, NL-9713 AV, Netherlands
- dTelomere and Genome Stability Laboratory, Instituto Gulbenkian de Ciência, Oeiras, 2781-901, Portugal
- eTelomere Shortening and Cancer Laboratory, Institute for Research on Cancer and Aging (IRCAN), UMR7284, U1081, UNS, Nice, 06107, France
- fDivision of Cell Biology and Cancer Genomics Center, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, Netherlands
- gCell Division Unit, Faculty of Medicine, Department of Experimental Biology, Universidade do Porto, Porto, 4200-319, Portugal
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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. © 2018, The Author(s).
Indexed keywords
| EMTREE drug terms: | forkhead box protein M1forkhead box protein M1FOXM1 protein, human |
|---|---|
| GEOBASE Subject Index: | agingcellchromosomegene expressionmolecular analysisphenotypeploidysenescence |
| EMTREE medical terms: | adolescentadultageagedaginganeuploidyanimal cellArticlecell agingcell cycle G2 phasecell divisionchildcontrolled studycorrelation analysisfeedback systemfemalefibroblastgene expressionhumanhuman cellHutchison Gilford progeria syndromeinfantlive cell imagingmalemiddle agedmitosismousenewbornnonhumanphenotypeprogeriaschool childsenescencetime lapse imagingvery elderlyagingCaucasiancytologyethnologyG2 phase cell cycle checkpointgene expression regulationgeneticsmetabolismpathologypreschool childprimary cell culture |
| MeSH: | AdolescentAdultAgedAged, 80 and overAgingAneuploidyCellular SenescenceChildChild, PreschoolEuropean Continental Ancestry GroupFibroblastsForkhead Box Protein M1G2 Phase Cell Cycle CheckpointsGene Expression Regulation, DevelopmentalHumansInfantMaleMiddle AgedMitosisPrimary Cell CultureProgeria |
Chemicals and CAS Registry Numbers:
Forkhead Box Protein M1; FOXM1 protein, human
Funding details
| Funding sponsor | Funding number | Acronym |
|---|---|---|
| IF/00916/2014 | ||
| China National Funds for Distinguished Young Scientists | PTDC/BEX-BCM/ 2090/2014,NORTE-01-0145-FEDER-000029 | |
| KWF Kankerbestrijding | 2012-RUG-5549 | |
| European Regional Development Fund | ON.2,NORTE-07-0124-FEDER-000003,POCI-01-0145-FEDER-007274 | |
| 2020/PORTUGAL 2020 | ||
| Ministério da Ciência, Tecnologia e Ensino Superior | Superior | |
| E.L. Wiegand Foundation | ||
| NORTE2020 |
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1
We thank H. Maiato, J.M. Cabral, and J. Bessa at i3S for critical discussions and reading of the manuscript; P. Sampaio and A. Maia for technical help with Advanced Light Microscopy. E.L. holds an FCT Investigator Postdoctoral Grant (IF/00916/2014) from FCT/MCTES (Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior). FCT Fellowships (SFRH/BD/74002/2010; SFRH/BD/125017/2016; PD/BD/128000/2016) supported J.C.M., S.V., and R.R. The following project grants supported this work: National Funds through FCT under the project PTDC/BEX-BCM/ 2090/2014 ; NORTE-01-0145-FEDER-000029 funded by North Regional Operational Program (NORTE2020) under PORTUGAL 2020 Partnership Agreement through Regional Development Fund (FEDER); NORTE-07-0124-FEDER-000003 co-funded by North Regional Operational Program (ON.2) through FEDER and by FCT; and POCI-01-0145-FEDER-007274 i3S framework project co-funded by COMPETE 2020/PORTUGAL 2020 through FEDER and by FCT; Foundation Pediatric Oncology Groningen grant and Dutch Cancer Society grant 2012-RUG-5549 to F.F.
- ISSN: 20411723
- Source Type: Journal
- Original language: English
- DOI: 10.1038/s41467-018-05258-6
- PubMed ID: 30026603
- Document Type: Article
- Publisher: Nature Publishing Group
Logarinho, E.; Aging and Aneuploidy Laboratory, IBMC, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal;
© Copyright 2018 Elsevier B.V., All rights reserved.
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