ena-STUDY-EUROPEAN RESEARCH INSTITUTE FOR THE BIOLOGY OF AGEING, UNIVERSITY OF GRONINGEN, UNIVERSITY MEDICAL CENTER GRONINGEN-31-05-2018-09:57:48:068-443
RNA-sequencing of human dermal fibroblasts (wild-type, overexpressing FoxM1, and with FoxM1 knock-down).
Aneuploidy, a condition in which the number of chromosomes in a cell is not an exact multiple of the haploid set, has been linked to aging and age-associated diseases. This association has been well-documented for oocytes and is the main cause of miscarriage and birth defects in humans. Aneuploidy has been also reported for elderly somatic cells, but the molecular mechanisms remain unknown. Here, we show that aneuploidy increases with natural aging due to transcriptional downregulation of several mitotic genes leading to cumulative dysfunction of the mitotic machinery. Live cell imaging of mitosis in primary dermal fibroblasts isolated from young, middle-aged and old-aged humans and mice revealed that mitotic duration increases with advancing age alongside with chromosome segregation defects. This age-associated loss of mitotic fidelity correlated with the steady repression of Forkhead box M1 (FoxM1), the transcription factor that drives the expression of many G2/M cell cycle genes. Indeed, expression of a constitutively active form of FoxM1 restored mitotic gene levels in old cells and, importantly, prevented both aneuploidy and cellular senescence. Finally, we found that the majority of senescent elderly fibroblasts were aneuploid, suggesting cellular senescence as the major outcome of age-associated aneuploidy. Thus, our work opens up the possibility of modulating mitotic efficiency through FoxM1 to delay aging.
Aneuploidy, a condition in which the number of chromosomes in a cell is not an exact multiple of the haploid set, has been linked to aging and age-associated diseases. This association has been well-documented for oocytes and is the main cause of miscarriage and birth defects in humans. Aneuploidy has been also reported for elderly somatic cells, but the molecular mechanisms remain unknown. Here, we show that aneuploidy increases with natural aging due to transcriptional downregulation of several mitotic genes leading to cumulative dysfunction of the mitotic machinery. Live cell imaging of mitosis in primary dermal fibroblasts isolated from young, middle-aged and old-aged humans and mice revealed that mitotic duration increases with advancing age alongside with chromosome segregation defects. This age-associated loss of mitotic fidelity correlated with the steady repression of Forkhead box M1 (FoxM1), the transcription factor that drives the expression of many G2/M cell cycle genes. Indeed, expression of a constitutively active form of FoxM1 restored mitotic gene levels in old cells and, importantly, prevented both aneuploidy and cellular senescence. Finally, we found that the majority of senescent elderly fibroblasts were aneuploid, suggesting cellular senescence as the major outcome of age-associated aneuploidy. Thus, our work opens up the possibility of modulating mitotic efficiency through FoxM1 to delay aging.