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

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.

Description

This deposit is composed by a publication in which the IGC's authors have had the role of collaboration (it's a collaboration publication). This type of deposit in ARCA is in restrictedAccess (it can't be in open access to the public), and can only be accessed by two ways: either by requesting a legal copy from the author (the email contact present in this deposit) or by visiting the following link: https://www.nature.com/articles/s41467-018-05258-6
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Keywords

Aneuploidy Chromosome segregation Mechanisms of disease Senescence

URI

http://hdl.handle.net/10400.7/888

Citation

Macedo, J.C., Vaz, S., Bakker, B., Ribeiro, R., Bakker, P.L., Escandell, J.M., Ferreira, M.G., Medema, R., Foijer, F., Logarinho, E. (2018). FoxM1 repression during human aging leads to mitotic decline and aneuploidy-driven full senescence. Nat Commun. 9(1):2834.