RT Journal Article
SR Electronic
T1 Molecular basis of mitotic decline during human aging
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 261008
DO 10.1101/261008
A1 Joana Catarina Macedo
A1 Sara Vaz
A1 Bjorn Bakker
A1 Rui Ribeiro
A1 Petra Bakker
A1 Jose Miguel Escandell
A1 Miguel Godinho Ferreira
A1 René Medema
A1 Floris Foijer
A1 Elsa Logarinho
YR 2018
UL http://biorxiv.org/content/early/2018/02/06/261008.abstract
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.