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How it works
Senescent cells are somatic cells, other than reproductive cells, that can no longer divide, but are resistant to apoptosis (Scudellari, 2017). Although these cells have no use, they do not die off, which gives them their trivial name of “zombie cells”. Zombie cells can exist in various parts of the body, and they all have their own specific resistance to apoptosis, express different extracellular proteins, and secrete different variations of molecules such as cytokines (Scudellari, 2017). This senescence secretion activity is described as the cell’s senescence-associated secretory phenotype (SASP). The accumulation of zombie cells and SASP’s can cause many varied results (Coppé, Desprez, Krtolica, & Campisi, 2010). Senescent cells die off to protect against the damage that has been done to it, which could cause cancer. While this is helpful, instead of dying off, zombie cells become inactive and accumulate in the body. Recent discoveries suggest that the accumulation of the cells in the body are related to ageing and age related disorders.
Gene mutations in the DNA of normal cells are the cause of cancer. On the telomeres of DNA, there are two genes in which cancer can be suppressed by, called tumor suppressor genes. These two genes can be broadly classified as gatekeepers and caretakers. Gatekeeper genes are genes that control or inhibit cell growth (Campisi 2003; Campisi 2005). These cells work by completely eliminating potentially cancerous cells by withdrawing the cell from the cell cycle. The damage or loss of either or both copies of the suppressor gene lead to uncontrolled growth, known as tumors (Deininger, 1999). Some hereditary links of cancer are traced back to these mutations of tumor suppression genes on DNA chromosomes. Caretaker genes prevent cancer by using methods to avoid DNA damage and/or optimize DNA repair (Campisi 2003; Campisi 2005). These genes are goal-oriented to keep the other cells healthy, suppressing mutation. As do gatekeepers, caretakers also play a role in the cell cycle. Caretaker genes review the DNA before replication, they can then pause the cycle to allow DNA repair, or if the DNA is too damaged, the gene signals apoptosis, which is programmed cell death (Campisi, 2005). With caretaker genes come a major downfall in its role of DNA repair. If the repair of a gene require deletion of duplication, the gatekeeper gene could be included in that repair. The deletion of DNA could delete the gatekeeper gene and would stimulate aggressive cell growth, and the duplication of DNA could increase the number of proto-oncogenes, which are normal genes that are transformed into oncogenes (cancer cells) by mutation. Senescence is typically caused by the gatekeeper genes and inhibited by caretaker genes. While these cells are preventing cancerous growths, the damaged cell is not being terminated, it is just accumulates in the body.
How it works
The two common pathways of gatekeeper genes that induce senescence are caused by the proteins p53 and pRB (Bringold &Serrano, 2000; Campisi, 2003). P53 is a gene that regulates the cell cycle and serves as a leader at the checkpoint that finds telomere mutations and oncogenes. This gene has been described as “the guardian of the genome” due to its role in the inhibition of genome mutation (Toufektchan & Toledo, 2018). Fifty percent of all human tumors include the disruption of p53, its importance in suppressing tumor growth is evident in this (Hickman, 2002). The p53 pathway is carried out as the following; dysfunctional telomeres or oncogenes jumpstart distress and damage a cell’s DNA, p53 then acts as the guardian to filter these cells out of the cell cycle before the cell participates in mutation, p53 acts by signaling specific transcription genes (which includes the production of protein p21) to induce senescence growth (Beausejour, 2003; Campisi, 2005; Hickman, 2002). The loss of p53 pathways delay the transcription of target genes that induce the aggregation of senescence cells. This means that the checkpoint at which mutations and oncogenes are being filtered at is not activated. Not only does this prevent the replication of senescent cells to combat tumorigenesis, in addition, some senescent cells go through a complete reversal and resume growth.
The protein pRB is a repressor of heterochromatin tumor-causing targets and sometimes of other growth-promoting genes (Beausejour, 2003). The pathway of pRB also includes the incorporation of the positive regulator p16, which also has its own suppression traits. Protein p16 is induced by cell stress and oncogenes, this increase in p16 prompts the activation of pRB, which then repairs or rearranges the damaged chromatin, and develops senescent cells (Campisi, 2005; Hickman, 2002). Unlike the p53 pathway, no damage can reverse the results of the pRB pathway. The loss of pRB pathways rise from issues with protein p16; cells may spontaneously silence or reduce p16 due to unusual epithelial cells.
Apoptosis and senescence are both inclined to cease tumor growth; apoptosis by cell termination and senescence by cell impedance (Green & Evan, 2002). Though these functions have similar end goals, they contrast in various ways. Both processes act in response to biological stressors; senescence responds to less detrimental damage than apoptosis does (Vousden, & Lu 2002; Childs, Durik, Baker, & Deursen, 2015). Some stressors at low doses lead to senescence while higher doses of that same stressor lead to apoptosis, or, these processes could respond to stressors of completely different cells (Childs, Durik, Baker, & Deursen, 2015). Senescence could also be induced if the ability for the cell to go through with apoptosis. While apoptosis dismembers the entire cell and rids it of the cell cycle and body, senescence keeps gene, shuts the cell off, but leaves the lifeless cell in the body. The cell then releases senescence-associated secretory phenotypes, which can include pro-inflammatory growth factors that could affect other cells. The p53 pathway of tumor suppression can access apoptosis or senescence to prevent the cell from participating in tumorigenesis, however, the cell’s decision to activate apoptosis or senescence is not clearly understood (Zuckerman, Wolyniec, Sionov, Haupt S., & Haupt Y., 2009).
Apoptosis is a necessary component of normal bodily homoeostasis. Cells must die every day in order to balance out the number of new cells being made. Apoptosis is responsible for killing off cells for regulation and also in finding damaged cells and removing them. The cells surrounding the cell being encapsulated by apoptosis are unaffected due to the death programming including cells that clean up the enzymes released from the destruction (Campisi, 2003). The rotation of good cells coming in and bad cells leaving out gives apoptosis a large role in normal tissue function (Campisi, 2003). Without apoptosis, mutant cells would be abundant, such as in the case of cancer. While apoptosis assists in preventing cancer, if the body misuses apoptosis it could be potentially dangerous. Underactive or overactive use of apoptosis could cause tissue atrophy or degeneration (Campisi, 2003 & Martin, 2001). One particular defect of inadequate apoptosis is the aging component. In an older adult, if apoptosis is moving quicker than the remaking of new cells, new stem cells in the body begin to be destroyed. This commonly happens to the neurons of elderly organisms, resulting in neurodegeneration (Campisi, 2003). Contrarily, if apoptosis is moving slower than required, mutant cells can still actively participate in tumorigenesis and accrue because they are not being destroyed quickly enough.
While senescent cells work to suppress tumors, their presence in the body affects other cells via their senescence-associated secretory phenotype (SASP). Senescent cells are no longer in action, yet they still exist and secrete SASP’s. The affect that the SASP have on other cells make it difficult to determine if the good efforts of senescent cells outweigh the bad they could potentially convey. SASP molecules can be soluble or insoluble and can affect surrounding cells in ways such as signal transmission and cell receptors (Coppé, Desprez, Krtolica, & Campisi, 2010). The most common of the soluble SASP molecules is the cytokine interlerkin-6 (IL-6) receptors (Coppé, Desprez, Krtolica, & Campisi, 2010). IL-6 displays pleiotropic characteristics in response to inflammation, immunity, and disease, yet has been associated with DNA damage. (Tanaka, Narazaki, & Kishimoto, 2014). The expression of IL-6 via SASP affects the DNA of surrounding cells; if the damage is detrimental, senescent cells will continue to accumulate, conversely, if the p53 pathway is not be able to filter the DNA damage, the cell will begin tumorigenesis. The cells surrounding senescent cells also have the potential of encoding the proteins released by SASP, altering structure and function of the cell.
An article by author Megan Scudellari is titled “To stay young, kill zombies”, this is a clever way of depicting the relationship between senescent cells and ageing. It is being heavily researched and there is some evidence that there are aspects of senescent cells that are related to accelerated ageing. The p53 is one aspect being researched upon. Researcher Tyner and colleagues conducted research on the p53 pathway by creating a mutant version of p53 that became abundant in the mice being tested; the mice were completely resistant to tumor growth (Tyner, Venkatachalam, Choi, Jones, Ghebranious, Ingelmann, et. al 2002). The mutant p53 mice had no signs of tumor growth, yet, their life span was significantly shorter than a non-mutant mice, and had signs of aging that the non-mutant mice did not have, such as weight loss and hunchback spine (Hinkal, Gatza, Parikh, & Donehower, 2009; Tyner, Venkatachalam, Choi, Jones, Ghebranious, Ingelmann, et. al 2002). Hyperactive p53 in the mice mean that there was an increase in p53 apoptosis and senescence . These results suggest that preventing cancer by altering senescence cell production result in accelerated aging. The pRB pathway is not as well researched as p53, but so far, it is assumed that since both pathways yield senescence cells, that pRB plays a role as well, it is just not as well defined.
The protein p16 from the pathway pRB, has been used as an indicator of when senescence has taken place. In age-related issues such as skin ulcers and arthritic joints, p16 is found, giving evidence that senescent cells are present factors in these defects. Another age-related involvement of senescent cells is their role in body tissues. Tissues have relatively constant amounts of cells, the accrual of nondividing senescent cells hinder tissue renewal and repair (Campisi, 2005). If damaged cells are being rescinded by senescence, the SASP could affect the healthy cells that are left, and damage those as well. In essence, senescence works well for suppressing tumorigenesis, but has tendencies to affect the other cells around them; options to assist age-related difficulties such as stem cell replacement are not viable because senescence could repeat the same cycle.
Zombie cells are a true representation of their nickname; they are the living dead, constantly around with no real genetic makeup. However, the way these cells aid in the suppression of tumor growth is a component that cannot be overlooked. From what is known about senescence cells so far, aging is an issue behind why these cells are not yet viable to be used in the advancement of cancer-related medicine. If the aging component of these cells from their SASP can be controlled, it is a possibility that senescence cells can be the foundation of groundbreaking medicine.
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