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Article Dans Une Revue Nature Communications Année : 2018

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

Joana Catarina Macedo
  • Fonction : Auteur
Sara Vaz
  • Fonction : Auteur
Bjorn Bakker
  • Fonction : Auteur
Petra Lammigje Bakker
  • Fonction : Auteur
Jose Miguel Escandell
  • Fonction : Auteur
René Medema
  • Fonction : Auteur
Floris Foijer
Elsa Logarinho
  • Fonction : Auteur

Résumé

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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Dates et versions

hal-02438802 , version 1 (26-11-2020)

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Joana Catarina Macedo, Sara Vaz, Bjorn Bakker, Rui Ribeiro, Petra Lammigje Bakker, et al.. FoxM1 repression during human aging leads to mitotic decline and aneuploidy-driven full senescence. Nature Communications, 2018, 9 (1), ⟨10.1038/S41467-018-05258-6⟩. ⟨hal-02438802⟩
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