Fig. 2: Mechanisms regulating cellular senescence.

Senecence triggers include DDR/Telomeres shortening; Oncogenic signals/ Tumor suppressor inactivation; ROS(Non-mitochondrial and mitochondrial source of ROS); MiDAS-Dysfunctional mitochondria; Paracrine senescence. These triggers activate cell cycle protein kinase inhibitors p16INK4A and p21Cip1 by modulating their respective signaling pathways. Elevated expression of these inhibitors leads to the inhibition of cell cycle protein-dependent kinases CDK2 and CDK4/6. Consequently, this inhibition promotes the continuous association of RB with the transcription factor E2F, thereby maintaining RB in a hypophosphorylated state. This prevents E2F from exerting its regulatory role in the cell cycle, ultimately causing cell cycle arrest at the G1 phase.