The emerging role of senescent cells in tissue homeostasis and pathophysiology

Abstract

Cellular senescence is a state of permanent growth arrest and is thought to play a pivotal role in tumor suppression. Cellular senescence may play an important role in tumor suppression, wound healing, and protection against tissue fibrosis in physiological conditions in vivo. However, accumulating evidence that senescent cells may have harmful effects in vivo and may contribute to tissue remodeling, organismal aging, and many age-related diseases also exists. Cellular senescence can be induced by various intrinsic and extrinsic factors. Both p53/p21 and p16/RB pathways are important for irreversible growth arrest in senescent cells. Senescent cells secret numerous biologically active factors. This specific secretion phenotype by senescent cells may largely contribute to physiological and pathological consequences in organisms. Here I review the molecular basis of cell cycle arrest and the specific secretion phenotype in cellular senescence. I also summarize the current knowledge of the role of cellular senescence in vivo in physiological and pathological settings.

Keywords: age-associated diseases; cell proliferation; cellular senescence; immortalization; inflammation; senescence-associated secretory phenotype.

Fig. 1

Schematic diagram of cell cycle arrest in senescent cells. (a) Diploid senescent cells. In response to various intrinsic and extrinsic stimuli such as telomere erosion, DNA damage, oxidative stress, and activated oncogene overexpression, cells enter a senescent state. In senescent cells, CDK inhibitors, p21 and p16, are upregulated and the Rb protein is maintained in the active state. Active Rb inhibits the transition from the G1 to S phase of the cell cycle. (b) Tetraploid senescent cells. At the G2 phase of cell cycle, the p53/p21 pathway is activated in the cells exposed to senescence, inducing stimuli. APC/C^Cdh1 is prematurely activated via the accumulation of p21, and mitosis skip occurs in these cells. The Rb family of proteins is also important for the induction and maintenance of senescence.