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Mitotic decline during aging leads to aneuploidy and cellular senescence

ABSTRACT: RNA-sequencing of human dermal fibroblasts (wild-type, overexpressing FoxM1, and with FoxM1 knock-down).

PROVIDER: PRJEB27047 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR2608900.fastq.gz	Fastqsanger.gz
	ERR2608910.fastq.gz	Fastqsanger.gz
	ERR2608892.fastq.gz	Fastqsanger.gz
	ERR2608894.fastq.gz	Fastqsanger.gz
	ERR2608914.fastq.gz	Fastqsanger.gz

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

Project description: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.

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