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FoxM1 repression during human aging leads to mitotic decline and aneuploidy-driven full senescence
Macedo, J. C., Vaz, S., Bakker, B., Ribeiro, R., Bakker, P. L., Escandell, J. M., Ferreira, M. G., Medema, R., Foijer, F. & Logarinho, E., 19-Jul-2018, In : Nature Communications. 9, 1, 17 p., 2834.Research output: Contribution to journal › Article › Academic › peer-review

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- FoxM1 repression during human aging leads to mitotic decline and aneuploidy-driven full senescence
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DOI
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.
Original language | English |
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Article number | 2834 |
Number of pages | 17 |
Journal | Nature Communications |
Volume | 9 |
Issue number | 1 |
Publication status | Published - 19-Jul-2018 |
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