Document details

FoxM1 repression during human aging leads to mitotic decline and aneuploidy-driven full senescence

Author(s): Macedo, Joana Catarina ; Vaz, Sara ; Bakker, Bjorn ; Ribeiro, Rui ; Bakker, Petra Lammigje ; Escandell, Jose Miguel ; Ferreira, Miguel Godinho ; Medema, René ; Foijer, Floris ; Logarinho, Elsa

Date: 2018

Persistent ID:

Origin: ARCA - Access to Research and Communication Annals

Project/scholarship: info:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBD%2F74002%2F2010/PT;

Subject(s): Aneuploidy; Chromosome segregation; Mechanisms of disease; Senescence


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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Document Type Journal article
Language English
Contributor(s) Macedo, Joana Catarina; Vaz, Sara; Bakker, Bjorn; Ribeiro, Rui; Bakker, Petra Lammigje; Escandell, Jose Miguel; Ferreira, Miguel Godinho; Medema, René; Foijer, Floris; Logarinho, Elsa
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