PT  - JOURNAL ARTICLE
AU  - Joana Catarina Macedo
AU  - Sara Vaz
AU  - Bjorn Bakker
AU  - Rui Ribeiro
AU  - Petra Bakker
AU  - Jose Miguel Escandell
AU  - Miguel Godinho Ferreira
AU  - René Medema
AU  - Floris Foijer
AU  - Elsa Logarinho
TI  - Molecular basis of mitotic decline during human aging
AID  - 10.1101/261008
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 261008
4099  - http://biorxiv.org/content/early/2018/02/06/261008.short
4100  - http://biorxiv.org/content/early/2018/02/06/261008.full
AB  - Aneuploidy, an abnormal chromosome number, has been linked to aging and age-associated diseases, but the underlying molecular mechanisms remain unknown. Supported by direct live-cell imaging of young, middle-aged and old-aged primary human dermal fibroblasts, we found that aneuploidy increases with aging due to general dysfunction of the mitotic machinery. Increased chromosome segregation defects in elderly mitotic cells correlated with an early senescence-associated secretory phenotype (SASP) and repression of Forkhead box M1 (FoxM1), the transcription factor that drives expression of most G2/M genes. By restoring FoxM1 levels in elderly and Hutchison-Gilford Progeria Syndrome fibroblasts we prevented aneuploidy and, importantly, ameliorated cellular phenotypes associated with aging. Moreover, senescent fibroblasts isolated from elderly donors’ cultures were mostly aneuploid, suggesting that aneuploidy is a key player in the progression 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.