Therapeutic Elimination of Senescent cells

The persistence and accumulation of senescent cells has been shown to potentially play a role in the pathophysiology of ageing and age-related disease. Therefore, the elimination of senescent cells from tissues has the potential to increase health-span and possibly even lifespan. For example, it was recently demonstrated that the elimination of p16- expressing cells in a transgenic mouse model delays age-associated disorders. As such, there are a number of therapeutic avenues of research that have the potential to eliminate senescent cells or prevent their accumulation. Firstly, telomerase activators could be used to extend telomere length, thereby extending the replicative capacity of cells and preventing RS. Secondly, cellular reprogramming refers to the potential of reverting senescent cells back to their normal functioning state. Alternatively, if quiescent cells inflicted with DNA damage convert to senescence when stimulated to proliferate, then eliminating such damage may prevent this conversion. Thirdly, if senescent cells indeed accumulate due to failure of removal by an ageing immune system, then enhancing the immune response to senescent cells may improve their elimination. Finally, identification of pharmacological compounds that can specifically induce programmed cell death in senescent cells will provide an effective means for targeting senescent cells regardless the reason of their presence. However, the potential use of future pharmacological compounds should be taken with caution, since senescent cells also play a beneficial role during wound healing. Prematurely eliminating senescent cells during tissue damage may impair the wound response. In fact, it can be speculated that a tradeoff may exist between senescent cell removal and wound healing, whereby enhanced senescent cell removal (and possibly slower ageing) results in a slower healing process (and increase risk of infectious disease). Future research will show if pharmacological elimination of senescent cells is a good avenue for treatment of age-related disorders and health-span extension.

Link: Physiological and pathological consequences of cellular senescence

Immune surveillance of senescent cells

Taken from: Physiological and Pathological Consequences of Cellular Senescence

The ability of senescent cells to trigger an innate immune response via the up-regulation of pro-inflammatory cytokines was first suggested to play a role in limiting tumourigenesis. This immune response was later shown to be important in the elimination of senescent stellate cells during liver damage. In natural killer (NK) cell mediated cytotoxicity, NK cells identify senescent cells by the presence of NKG2D ligands on the membrane of senescent cells. The presentation of these ligands on senescent cells might be mediated by a DDR, which was previously shown to induce their expression. In particular, it appears that the ATM-ATR pathway is important for the up-regulation of NKG2D ligands in response to stress. NK cell induced cytotoxicity of senescent cells is mediated by granule exocytosis and perforin-mediated death rather than death-receptor-induced apoptosis. The perforin mediated cytotoxicity decreases in humans with age, and might therefore contribute to accumulation of senescent cells in the organism during ageing and in age-related diseases. As discussed, senescent cells are known to accumulate with age and in disease states, suggesting that senescent cells may be evading immune surveillance or their rate of accumulation is greater than the rate of removal or both. It has been advocated that the accumulation of senescent cells with age might be the consequence of an impaired ageing immune system. In fact, immune cells can also become senescent and these changes may contribute to impaired elimination of senescent cells. Therefore, strategies to restore an ageing immune system are a compelling approach for the elimination of senescent cells and for promoting an increased health-span.

A recent study has shown that senescent HSCs can be eliminated by another component of the innate immune system, the M1-like macrophages during liver damage and tumorigenesis in the liver. Secretory factors from senescent HSCs were shown to aid the elimination of these cells by macrophages. In contrast, cells that could not become senescent due to deletion of p53 and were not targeted by macrophages. Therefore, the innate immune system appears to be an initial early barrier that regulates the presence of senescent cells in physiological conditions such as in wound healing. 

The elimination of senescent cells by the adaptive immune system has also been demonstrated. OIS hepatocytes were shown to secrete cytokines to evoke an immune response leading to the elimination of senescent cells by CD4(+) T-cells, a process which required the action of macrophages. The elimination of senescent hepatocytes was required to prevent the development of liver cancer. This study mentions the attraction of T-cells by soluble factors but not the mechanism of senescent cell recognition, an area of research that still needs to be explored. However, there is some indication that RS cells may up-regulate MHC1 expression, possibly via p53. It can be speculated that MHC1 proteins in senescent cells may function to display senescence-associated antigens similar to cancer cells, allowing recognition and elimination by cytotoxic T-cells. Further research will provide multiple insights into the mechanisms and consequences of the interaction of senescent cells with the immune system.

Detecting Senescent Cells: Biomarkers

The standard SA-beta-gal staining, while indicative of the presence of senescent cells, is not an absolute marker for senescent cell and indicates increased lysosmal b-galactosidase activity. The use of several molecular markers that represent different characteristics of senescent cells is necessary (see figure). Such molecular markers can represent the cell cycle arrest machinery (e.g. p53, p21, p16), lack of cellular proliferation (e.g. lack of BrdU incorporation, Ki67), activation of the DDR (e.g. gamamH2AX or p53BP1 foci), expression of secretory factors (e.g. IL-6 and IL-8), the activation of the pathways that regulate the secretory phenotype (e.g. p-p65 or p-p38), the activation of immune surveillance-related genes and possible regulators for their pro-survival response (DCR2, p-Akt, p-Erk).

Link: Physiological and pathological consequences of cellular senescence

Reclassifying Cellular Senescence into Two Main Types

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.  

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