Feedback regulation between FOXM1 and APC/CCdh1 determines the changes in cell cycle dynamics during aging

Abstract

Aging is characterised by a loss of regenerative capacity, though it remains elusive how aged proliferating cells slowdown cycling eventually becoming senescent. We previously found that repression of the FOXM1 transcription factor accounts for mitotic decline during aging due to a global transcriptional shutdown of mitotic genes in proliferating cells. Intriguingly, a 1.5-fold increase in both cell cycle and mitosis durations was observed in elderly cells in deviancy to a previous study showing mitosis to be temporally insulated from variability in earlier cell cycle phases due to the robustness of the positive feedback loop controlling CDK1-Cyclin B1 activity. Thus, we asked if molecular thresholds controlling cell cycle phase transitions become unfitted with aging. Here, we used live-cell imaging of primary human dermal fibroblasts of advancing age donors in combination with high-throughput image analysis, to investigate age-related changes in cell cycle dynamics. Interestingly, we found mitosis insularity to be gradually lost along aging due to defective switch-like activation of CDK1 at mitotic entry driven by FOXM1 repression. Moreover, we found the levels of FZR1/Cdh1 co-activator of APC/C, the E3-ubiquitin ligase directing the proteolytic degradation of FOXM1 at mitotic exit, to increase with advancing age. Importantly, FZR1/Cdh1 repression was shown to restore cell cycle fitness and FOXM1 levels in aged proliferating cells, preventing the accumulation of cell cycle inhibitors and senescence markers in their progeny. Thus, changes in FOXM1 and APC/CCdh1 interlinked activities account for the loss of proliferative capacity and senescence accrual during aging, thereby delivering useful markers and/or targets to explore in anti-aging approaches.