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

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

Nature communications (2018-07-22)
Joana Catarina Macedo, Sara Vaz, Bjorn Bakker, Rui Ribeiro, Petra Lammigje Bakker, Jose Miguel Escandell, Miguel Godinho Ferreira, René Medema, Floris Foijer, Elsa Logarinho
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Fibronectin bovine plasma, solution, sterile-filtered, BioReagent, suitable for cell culture
Sigma-Aldrich
Monoclonal Anti-α-Tubulin antibody produced in mouse, clone B-5-1-2, ascites fluid