Figure 3

Senescence is a multi-layered process involving interactions between the DNA damage response, reactive oxygen species and senescence-associated secretory phenotype. (a) Initially, stressors such as telomeric and non-telomeric DNA damage can lead to activation of a DNA damage response (DDR) and cell cycle arrest. Following activation of the DDR, p53, p21 and p38MAPK pathways have been shown to enhance nuclear factor (NF)-κB transcriptional activity. NF-κB activation is both responsible for the senescence-associated secretory phenotype (SASP) and can induce (and be activated) by reactive oxygen species (ROS). p16 has been shown to induce ROS generation via NADPH oxidases [62]; however, it has been shown to be unrelated to the SASP [88]. Secretion of bioactive molecules such as ROS and SASP factors contribute not only to reinforce senescence in an autocrine fashion, but also to induce senescence in neighbouring cells. (b) Components of the SASP (such as IL-8, β-IFN and transforming growth factor (TGF)-β) have been shown to reinforce the senescence arrest via ROS through yet unidentified mechanisms [21, 22, 89]. (c) NF-κB transcriptional activity has been shown to be dependent on the DDR and ROS. However, NF-κB activation has been shown to increase ROS generation (via regulating expression of mitochondrial genes or antioxidant, pro-oxidant genes) [96, 97]. DDF - DNA Damage Foci.