Autor(es): Macedo, Joana Catarina ; Vaz, Sara ; Bakker, Bjorn ; Ribeiro, Rui ; Bakker, Petra Lammigje ; Escandell, Jose Miguel ; Ferreira, Miguel Godinho ; Medema, René ; Foijer, Floris ; Logarinho, Elsa
Data: 2018
Identificador Persistente: http://hdl.handle.net/10400.7/888
Origem: ARCA - Access to Research and Communication Annals
Projeto/bolsa: info:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBD%2F74002%2F2010/PT;
Assunto(s): Aneuploidy; Chromosome segregation; Mechanisms of disease; Senescence
This deposit is composed by a publication in which the IGC's authors have had the role of collaboration (it's a collaboration publication). This type of deposit in ARCA is in restrictedAccess (it can't be in open access to the public), and can only be accessed by two ways: either by requesting a legal copy from the author (the email contact present in this deposit) or by visiting the following link: https://www.nature.com/articles/s41467-018-05258-6
This deposit is composed by the main article and the supplementary materials are present in the publisher's page in the following link: https://www.nature.com/articles/s41467-018-05258-6#Sec36
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.
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.
