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When cells become senescent in vitro they often become resistant to apoptotic stimuli in comparison to proliferating cells. It can be speculated that if immune cells are necessary for eliminating senescent cells, the pro-survival phenotype of senescent cells may function to favor such elimination. In conjunction with regulating immune ligands and the secretory phenotype, persistent activation of the DDR, particularly double strand breaks (DSBs), may also promote a pro-survival response to facilitate DNA repair. However, if senescent cells are not removed by the immune system, this pro-survival phenotype inadvertently promotes their persistence in tissues. Alternatively, the pro- survival phenotype of senescent cells may be an adaptive response mediated by stresses within the microenvironment to facilitate protection from further stress.
The question still arises as to why senescent cells may favor removal by the immune system rather than undergoing programmed cell death. One plausible explanation could be related to the potential function of senescent cells during cellular repair following tissue damage. During wound healing, senescent cells most likely play a positive role by (1) secreting chemo-attractants that recruit and activate immune cells to the site of injury, (2) secrete growth factors to stimulate cellular proliferation required for cellular replacement and protein synthesis and (3) the secretion of proteases to debride damaged tissue. In addition, senescent cells may help to preserve tissue integrity during wound healing, that may otherwise be lost if cells underwent apoptosis, until such time that non- resident cells from other sources, such as stem cells are present to repopulate the tissue with functional cells. In an orchestrated response, senescent cells would be subsequently eliminated by the immune system when no longer required.
The main molecular pathways of senescence, persistent DDR and Rb lead to sustained chromatin remodeling within senescent cells. This stochastic remodeling of chromatin in senescent cells most likely facilitates promiscuous gene expression associated with cell senescence. Promiscuous gene expression refers to changes in gene expression not normally associated with non- senescent counterparts of the same cell type. Promiscuous gene expression is often observed in microarray data and other analysis of gene expression of senescent verses their non- senescent counterparts and appears to also be cell-type specific. It is hypothesised that chromatin rearrangement would allow access to DNA normally tightly packed and restrict other areas of chromatin that are normally open. It has also been suggested that DNA damage may modulate gene expression by altering the binding capacity of transcription factors. In addition, changes in DNA methylation associated with cell senescence may also contribute to promiscuous gene expression. Therefore, genes that may normally be expressed can be suppressed and genes normally suppressed become expressed.
A negative consequence of promiscuous gene expression in senescent cells is impairment in cellular function, the inability of cells to carry out their designated normal processes. As a result, the accumulation of these dysfunctional cells most likely leads to tissue dysfunction which compromises tissue structure and function, promoting disease. For example, a study using Klotho-deficient mice, which exhibit an accelerated ageing-like phenotype, investigated whether preventing cell senescence improves health-span in these mice. Plasminogen activator inhibitor-1 (PAI-1) is elevated in Klotho- deficient mice and is a known regulator of cell senescence. Klotho-deficient mice deficient in PAI-1 was reported to delay the induction of cell senescence, extending median lifespan and preserving organ structure and function. Another example of senescent cells that can no longer undertake their normal function might include senescent pancreatic beta cells that have impaired insulin release during diabetes and senescent vascular endothelial cells that display decreased activity of nitric oxide synthase (NOS). NOS is important for the production of nitric oxide (NO) required for maintaining vascular homeostasis and a decrease in NO production is associated with increased risk of cardiovascular disease. Therefore, a better understanding of the differences in the phenotype of senescent cells of different cell-types in relation to their in vivo function, is required to better understand mechanisms of disease development.
PAI-1–regulated extracellular proteolysis governs senescence and survival in Klotho mice
In addition to providing a protective role in tumour suppression and tissue damage, senescent cells may also function in embryonic development. It was suggested that cell- cell fusion induced senescence might play a physiological function in the placenta, thereby aiding embryonic development. ERVWE1, a fusion protein involved in the formation of the syncytiotrophoblast of the placenta causes cell fusion and induction of cell senescence in both cancer cells and normal fibroblasts. Fusion induced senescence (FIS) in vitro and in vivo is accompanied by activation of a DDR, p53 and p16(INK4a) dependent pathways. ERVWE1 mediated physiological cell fusion during embryonic development forms the syncytiotrophoblast that serves as the maternal/fetal interface at the placenta. The question of why the senescence program may be useful in normal placental function remains to be answered. However, it can be suggested that the resistance of senescent cells to apoptosis is necessary to maintain the viability of the syncytiotrophoblast. In addition, secretion of proteases, that are normally associated with senescent cells, may function to maintain feto-placental homeostasis. Placental proteases are required for the metabolism of vasoactive and immunomodulating peptides, thereby controlling the exchange of peptide hormones across the placenta and metabolic breakdown of maternal nutrients. Cytokine production is another feature of senescent cells that may play important roles within the placenta. IL-8, one of the main cytokines secreted by senescent cells, is necessary for normal placental function . Cytokine secretion may help regulate placental growth during pregnancy in addition to protecting the foetus from pathological organisms and facilitating interaction with immune cells. Further research is necessary in order to understand the functional significance of the senescence program in the placenta.
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 elimination of senescence 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.
The presence of DNA damage and subsequent up-regulation of p16(INK4a) in quiescent cells in vivo may induce a pre-senescent state that converts to a full senescent state when cells are stimulated to proliferate. This suggests that DNA replication is required to induce a persistent DDR associated with cell senescence. For example, damage to skeletal muscle in normal young mice causes the activation of quiescent satellite cells (adult stem cells), which proliferate and undergo myogenic differentiation required for muscle repair. However, a recent study has shown that in geriatric mice (28-32 months of age), satellite cell activation is impaired and satellite cells instead convert from a pre-senescent state (quiescent cells with high p16(INK4a) expression) to a full senescent state (including a DDR) when stimulated to proliferate in response to injury. As such, the induction of senescent satellite cells with age can impair satellite muscle regeneration. This study suggests that senescent cells may accumulate in late life due to a conversion from quiescence to senescence (termed geroconversion) in response to a requirement for cells to replicate over time to regenerate tissue. In this model, more and more quiescent cells are likely to accumulate DNA damage over the life-time of an organism and are therefore more likely to become senescent when induced to proliferate later in life. Therefore, if quiescent cells inflicted with DNA damage convert to senescence when stimulated to proliferate, then eliminating such damage may prevent this conversion.
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.