Fig. 2: Cellular senescence signaling pathways.

The internal mechanism that leads to cellular senescence varies depending on the triggers and context. Several pathways contribute to the activation of cell-cycle inhibitors, inhibition of retinoblastoma protein (RB) phosphorylation, and cell-cycle arrest which is the main manifestation of cellular senescence. The production of various chemokines, inflammatory cytokines, growth factors, and extracellular matrix remodeling factors which are named “senescence-associated secretory phenotype” (SASP) is also another significant manifestation of cellular senescence. Cellular senescence can be divided into replicative senescence and stress-induced premature senescence(SIPS). (I) In replicative senescence, telomere shortening may trigger activation of ataxia telangiectasia mutated (ATM) or ataxia telangiectasia and RAD3-related protein (ATR) kinases, and result in p53 upregulation, and increased p21. (II) In stress-induced premature senescence, mitochondrial dysfunction and oxidative stress may activate the mitogen-activated protein kinase kinase (MKK3 and MKK6) pathway and their downstream effector p38, leading to the upregulation of p16, p53, and p21 level. DNA damage activates a signaling cascade via ATM/ATR kinases, p53 upregulation, and increased p21. In inflammation response, a component of the senescence-associated secretory phenotype (SASP) pathway named transforming growth factor-β (TGF-β), may upregulate p21 level through SMAD complexes. Lastly, oncogenic signaling or loss of tumor suppressors upregulates p16, p53, and p21 levels, mediated by RAS, MYC, and phosphoinositide 3-kinase (PI3K) and their downstream effectors ATM, ATR, and ARF.