Persistent activation of the DNA-damage response (DDR) can trigger cells to undergo cellular senescence, a state of irreversible, immune evoking, growth arrest. In such a way, cellular senescence can prevent tumourigenesis firstly by blocking cells from replicating and producing abnormal and potentially cancerous daughter cells and secondly by coordinating their removal by immune cells. Additionally, senescent cells can aid tissue repair by preventing extensive cellular proliferation leading to fibrosis, possibly triggered by replication stressed-induced DNA damage. However, if this orchestrated removal of senescent cells becomes dysregulated, then persistent senescent cells can promote tumourigenesis and tissue damage.
An aspect of the DDR in senescent cells is the induction of an array of secretory factors, including cytokines/chemokine’s, which are important in attracting/activating immune cells to their vicinity. When immune cells reach the locality of senescent cells, they can then specifically recognize them by the expression of immune ligands on the cell membrane, a process that may also be regulated primarily by the DDR. The specific ligands recognized and the mechanism of senescent cell death will then be dependent upon the type of immune cell interacting with the senescent cell.
However, cells induced to undergo permanent growth arrest in vitro by the overexpression of the cyclin dependent kinase inhibitor p16ink4a, do not develop an immune evoking secretory phenotype until the addition of DNA damage. If cells in physiological or pathological conditions can indeed undergo permanent cell cycle arrest in a p16 dependent, DDR-independent manner, then these cells are unlikely to evoke an immune response for their clearance. In support of this, a recent study demonstrated that cells overexpressing p14(ARF) in the epidermis of mice remained present for weeks after transgene silencing (Tokarsky-Amiel et al 2013). Even if p16-induced senescent cells do not display a pro-inflammatory phenotype, they can still cause physiological problems simply by their inability to proliferate, an essential feature required for tissue regeneration and maintenance. In this regard, the growth arrest and pro-inflammatory phenotype of senescent cells can be investigated separately to determine which feature is important in different physiological contexts.
Until the phenotype of p16-induced senescent cells in vivo have been researched more extensively, cellular senescence could be divided into two separate types. Firstly, immunogenic senescence related to a DNA damage response, consisting of a pro-inflammatory phenotype and the presence of immune ligands, triggered by telomere shortening, oncogene-activation, and chemical stressors. Secondly, sterile senescence which lacks a pro-inflammatory phenotype and the inability to evoke an immune response.
If this distinction is made, then studies focused on the effect of cellular senescence on ageing, disease and cancer development can better design their experiments and avoid confusion between conflicting results due to differences in the types of senescence used.