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

作者：Macedo Joana Catarina; Vaz Sara; Bakker Bjorn; Ribeiro Rui; Bakker Petra Lammigje; Escandell Jose Miguel; Ferreira Miguel Godinho; Medema Rene; Foijer Floris; Logarinho Elsa^*

来源：Nature Communications, 2018, 9(1): 2834.

DOI：10.1038/s41467-018-05258-6

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.

• 出版日期2018-7-19