Expansion and Cell-Cycle Arrest: Common Denominators of Cellular Senescence

Senescence markers are the result of cell-cycle arrest and expansion-stimulation signals. Senescent cells increase in vivo when cell-cycle arrest and expansion stimulation are present. Our model explains senescent markers in postmitotic and non-permanently arrested cells. Cellular senescence is a major driver of age-related diseases, and senotherapies are being tested in clinical trials. Despite its popularity, cellular senescence is weakly defined and is frequently referred to as irreversible cell-cycle arrest. In this article we hypothesize that cellular senescence is a phenotype that results from the coordination of two processes: cell expansion and cell-cycle arrest. We provide evidence for the compatibility of the proposed model with recent findings showing senescence in postmitotic tissues, wound healing, obesity, and development. We believe our model also explains why some characteristics of senescence can be found in non-senescent cells. Finally, we propose new avenues for research from our model. Cellular senescence is a major driver of age-related diseases, and senotherapies are being tested in clinical trials. Despite its popularity, cellular senescence is weakly defined and is frequently referred to as irreversible cell-cycle arrest. In this article we hypothesize that cellular senescence is a phenotype that results from the coordination of two processes: cell expansion and cell-cycle arrest. We provide evidence for the compatibility of the proposed model with recent findings showing senescence in postmitotic tissues, wound healing, obesity, and development. We believe our model also explains why some characteristics of senescence can be found in non-senescent cells. Finally, we propose new avenues for research from our model. an active process which prevents cell-cycle progression. Cell-cycle arrest can be temporary or permanent. Arrested cells show features of the cell-cycle phase in which they were arrested. factors which, upon reaching a threshold, lead to the induction of cell-cycle arrest: for example DNA damage, oncogene activity, telomere shortening, or the expression of checkpoint genes. an increase in the volume of an individual cell. a process which results in an increase in volume of a cell population. Expansion can be driven by an increase in the volume of individual cells (growth/trophia) and/or by an increase in cell number (driven by proliferation/plasia). factors which contribute to increased cell growth or number. For example: epidermal growth factor (EGF), platelet-derived growth factor (PDGF), fibroblast growth factor 2 (FGF2), and insulin-like growth factors 1 and 2 (IGF1 and IGF2), among many others. a cellular phenotype characterized by the presence of senescence markers without permanent cell-cycle arrest. an abnormal increase in cell volume. a non-degradable aggregate of oxidized lipids, covalently crosslinked proteins, oligosaccharides, and transition metals. factors which stimulate mitogenesis/proliferation. cells which exit irreversibly from the cell cycle and are in G0 phase. quiescent cells temporarily exit from the cell cycle and are in G0 phase. damaged, quiescent, or differentiated cells which are likely to become senescent upon exposure to expansion factors.