Figure 3. A number of inducers can act alone or in combination to push cells into the senescent cell fate through pathways involving p16INK4a/Rb, p53/p21, and likely other pathways.
Triggers may include DNA damage (e.g., telomere shortening and single- and double-strand breaks); oncogenic mutations (e.g., Ras, Myc, B-Raf); reactive metabolites (e.g., ROS, ceramides, fatty acids, high glucose); high mitogen and nutrient signals that increase mTOR activity; and proteotoxic stress (e.g., protein aggregation and unfolded proteins). These may contribute to widespread changes in gene expression and chromatin remodeling (heterochromatin formation) that underlie senescence-associated growth arrest, the SASP, and changes in morphology. In these respects, cellular senescence can be viewed as a cell fate reminiscent of differentiation, replication, or apoptosis (external and internal inducers, transcription factor cascades, gene expression changes and chromatin remodeling, leading to changes in function). Evidence is better for some of the initiators and mediators of senescence than for others, and future research is likely to uncover additional initiators and mediators. Intracellular autocrine loops reinforce progression to irreversible replicative arrest, heterochromatin formation, and initiation of the SASP over a matter of days to weeks. In addition to removing cells from the progenitor/stem cell pool, senescence may contribute to tissue dysfunction and chronic disease predisposition through the SASP and associated chronic sterile inflammation and degradation of the extracellular matrix.