Details

Autor(en) / Beteiligte

• Macedo, Joana Catarina
• Vaz, Sara
• Bakker, Bjorn
• Ribeiro, Rui
• Bakker, Petra Lammigje
• Escandell, Jose Miguel
• Ferreira, Miguel Godinho
• Medema, René
• Foijer, Floris
• Logarinho, Elsa

Titel

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

Ist Teil von

• Nature communications, 2018-07, Vol.9 (1), p.2834-17, Article 2834

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2018

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.