Too big not to fail: emerging evidence for size-induced senescence

Cellular senescence refers to a permanent and stable state of cell cycle exit. This process plays an important role in many cellular functions, including tumor suppression. It was first noted that senescence is associated with increased cell size in the early 1960s; however, how this contributes to permanent cell cycle exit was poorly understood until recently. In this review, we discuss new findings that identify increased cell size as not only a consequence but also a cause of permanent cell cycle exit. We highlight recent insights into how increased cell size alters normal cellular physiology and creates homeostatic imbalances that contribute to senescence induction. Finally, we focus on the potential clinical implications of these findings in the context of cell cycle arrest-causing cancer therapeutics and speculate on how tumor cell size changes may impact outcomes in patients treated with these drugs. Senescence is a permanent state of cell cycle arrest and plays an important role in development, aging, and cancer biology. Although senescent cells are known to be larger than proliferative cells, recent research has revealed that increased cell size is not only a consequence but also a cause of permanent cell cycle exit. This review illustrates how excess cell size alters normal cell physiology and contributes to senescence induction.image