期刊
NATURE COMMUNICATIONS
卷 9, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-05258-6
关键词
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资金
- FCT Investigator Postdoctoral Grant from FCT/MCTES (Fundacao para a Ciencia e a Tecnologia/Ministerio da Ciencia, Tecnologia e Ensino Superior) [IF/00916/2014]
- FCT Fellowships [SFRH/BD/74002/2010, SFRH/BD/125017/2016, PD/BD/128000/2016]
- National Funds through FCT [PTDC/BEX-BCM/2090/2014]
- North Regional Operational Program (NORTE2020) under PORTUGAL 2020 Partnership Agreement through Regional Development Fund (FEDER) [NORTE-01-0145-FEDER-000029]
- North Regional Operational Program (ON.2) through FEDER [NORTE-07-0124-FEDER-000003]
- FCT
- COMPETE 2020/PORTUGAL 2020 through FEDER [POCI-01-0145-FEDER-007274 i3S]
- Foundation Pediatric Oncology Groningen grant
- Dutch Cancer Society grant [2012-RUG-5549]
- Fundação para a Ciência e a Tecnologia [PD/BD/128000/2016, SFRH/BD/74002/2010, PTDC/BEX-BCM/2090/2014, SFRH/BD/125017/2016] Funding Source: FCT
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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