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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 journalArticleAcademicpeer-review

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 languageEnglish
Article number2834
Number of pages17
JournalNature Communications
Volume9
Issue number1
Publication statusPublished - 19-Jul-2018

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