Fig. 5. Senescence-associated secretory phenotype (SASP).

G1/S cell cycle block (marked by a cross) driven by p53 is accompanied by accumulation of Rb protein, a critical suppressor of G1/S transition. Rb-triggered up-regulation of lysosomal compartment stimulates mTOR. In turn, mTOR activates PGC1α, a transcription factor involved in mitochondrial biogenesis. Up-regulated mitochondrial compartment accompanied by increase in respiration leads to increased ROS formation. It is followed by DNA damage, a main trigger of the ATM-mediated activation of NFκB pathway, p53, and PGC1α. As a result, positive feedback loops are forming that lead to senescence. NFκB-regulated transcription program triggers elevation of cytokines, chemokines, metalloproteinases (MMPs), and other molecules secreted by senescent cells (senescence-associated secretory phenotype, SASP). The secreted molecules attract immune cells, which induce inflammation in tissues populated with senescent cells.