The Role of Senescent Cells in Ageing and Cancer Suppression

Senescent cells, often termed as "zombie cells," are somatic cells that, although no longer capable of dividing, display resistance to apoptosis, the process of programmed cell death (Scudellari, 2017). These cells accumulate in various body parts, exhibiting unique resistance to apoptosis, expressing distinct extracellular proteins, and secreting diverse molecules, including cytokines (Scudellari, 2017). This secretory activity is known as the cell's senescence-associated secretory phenotype (SASP).

The presence of zombie cells and their SASPs can lead to various outcomes (Coppé, Desprez, Krtolica, & Campisi, 2010). While the cessation of cell division in senescent cells acts as a protective mechanism against potential cancerous mutations, their persistence in the body poses challenges.

Recent studies suggest that the accumulation of these cells is intricately linked to the process of ageing and the onset of age-related disorders.

Tumor Suppressor Genes

The genesis of cancer is often attributed to gene mutations in the DNA of normal cells. Among the mechanisms that inhibit cancerous growth are tumor suppressor genes located on DNA telomeres. These genes are broadly categorized into gatekeepers and caretakers. Gatekeeper genes play a critical role in controlling or inhibiting cell proliferation by removing potentially cancerous cells from the cell cycle (Campisi, 2003; Campisi, 2005). The malfunction or loss of these genes often results in uncontrolled cell growth, leading to tumor formation (Deininger, 1999). Some hereditary cancer cases trace back to mutations in these tumor suppressor genes on DNA chromosomes. Caretaker genes, on the other hand, function to prevent cancer by minimizing DNA damage and optimizing DNA repair (Campisi, 2003; Campisi, 2005). Their role is pivotal in maintaining cellular health, as they oversee the DNA replication process, pausing it to enable repair or signaling apoptosis if the damage is irreparable (Campisi, 2005). However, the deletion or duplication of DNA during repair can inadvertently affect gatekeeper genes, potentially promoting aggressive cell growth and transforming normal genes into oncogenes, or cancer cells, through mutations.

Senescence Pathways

Two primary pathways of gatekeeper genes that induce senescence involve the proteins p53 and pRB (Bringold & Serrano, 2000; Campisi, 2003). The p53 gene, often described as "the guardian of the genome," regulates the cell cycle and identifies telomere mutations and oncogenes (Toufektchan & Toledo, 2018). It plays a crucial role in inhibiting genomic mutations, as evidenced by its disruption in fifty percent of all human tumors (Hickman, 2002). The p53 pathway functions by detecting distress and DNA damage caused by dysfunctional telomeres or oncogenes. It acts as a checkpoint, filtering these cells out of the cell cycle before they contribute to mutations, by signaling transcription genes, including the production of protein p21, to induce senescence (Beausejour, 2003; Campisi, 2005; Hickman, 2002). The absence of p53 pathways can delay the transcription of target genes, leading to the aggregation of senescent cells. Consequently, some senescent cells might reverse and resume growth.

Conversely, the pRB protein represses tumor-causing targets and certain growth-promoting genes (Beausejour, 2003). Its pathway involves the positive regulator p16, which is induced by cell stress and oncogenes. The increase in p16 activates pRB, repairing or rearranging damaged chromatin and developing senescent cells (Campisi, 2005; Hickman, 2002). Unlike the p53 pathway, the results of the pRB pathway are irreversible. Issues with protein p16, such as spontaneous silencing or reduction due to anomalous epithelial cells, can disrupt the pRB pathway.

Apoptosis and Senescence

Both apoptosis and senescence aim to halt tumor growth; apoptosis achieves this by terminating cells, while senescence impedes them (Green & Evan, 2002). Despite their similar objectives, these processes differ significantly. Both respond to biological stressors, with senescence reacting to less severe damage than apoptosis (Vousden & Lu, 2002; Childs, Durik, Baker, & Deursen, 2015). Stressors at low doses may induce senescence, whereas higher doses lead to apoptosis, or they may respond to entirely different cellular stressors (Childs, Durik, Baker, & Deursen, 2015). Senescence can also be induced if the cell's ability to undergo apoptosis is compromised. Apoptosis dismantles the entire cell, removing it from the cell cycle and the body, while senescence deactivates the cell but leaves it within the body, where it releases SASPs, potentially affecting other cells. The p53 tumor suppression pathway can access apoptosis or senescence to prevent tumorigenesis, but the cell's decision to activate either process remains unclear (Zuckerman, Wolyniec, Sionov, Haupt S., & Haupt Y., 2009).

Apoptosis in Ageing

Apoptosis is vital for maintaining bodily homeostasis, as it balances the daily turnover of cells. It regulates cell numbers by eliminating damaged cells without affecting surrounding cells, thanks to programmed death processes that involve cleaning up released enzymes (Campisi, 2003). This balance is crucial for normal tissue function (Campisi, 2003). Without apoptosis, mutant cells could proliferate, leading to cancer. However, dysregulated apoptosis can be detrimental. Overactive or underactive apoptosis can cause tissue atrophy or degeneration (Campisi, 2003 & Martin, 2001). Inadequate apoptosis is linked to ageing, as accelerated apoptosis in the elderly can result in neurodegeneration by destroying new stem cells, particularly neurons (Campisi, 2003). Conversely, insufficient apoptosis permits mutant cells to persist and proliferate, contributing to tumorigenesis.

Senescence and Ageing

While senescent cells suppress tumors, their SASPs can affect other cells, raising questions about whether their benefits outweigh potential harm. SASP molecules, both soluble and insoluble, can influence surrounding cells through signal transmission and cell receptors (Coppé, Desprez, Krtolica, & Campisi, 2010). Interleukin-6 (IL-6) is a common soluble SASP molecule known for its pleiotropic effects on inflammation, immunity, and disease, and it is associated with DNA damage (Tanaka, Narazaki, & Kishimoto, 2014). IL-6 expression via SASP can damage surrounding cells' DNA; if the damage is severe, senescent cells accumulate, and if the p53 pathway fails to filter DNA damage, tumorigenesis may begin. Neighboring cells can also encode proteins released by SASP, altering their structure and function.

An article by Megan Scudellari titled "To stay young, kill zombies" cleverly captures the link between senescent cells and ageing. Research is ongoing, with evidence suggesting aspects of senescent cells contribute to accelerated ageing. The p53 pathway is a focus of such research. Tyner and colleagues created a mutant p53 version in mice, making them resistant to tumors (Tyner, Venkatachalam, Choi, Jones, Ghebranious, Ingelmann, et al., 2002). Despite the absence of tumors, these mice had shorter lifespans and exhibited ageing signs like weight loss and a hunchback spine (Hinkal, Gatza, Parikh, & Donehower, 2009; Tyner et al., 2002). Hyperactive p53 increased apoptosis and senescence, suggesting that manipulating senescent cell production could accelerate ageing. Though less researched, the pRB pathway's role in senescence is presumed similar to p53, given both yield senescent cells.

The p16 protein from the pRB pathway indicates senescence occurrence, found in age-related conditions like skin ulcers and arthritis, suggesting senescent cells contribute to these issues. Senescent cells also impact body tissues, as their accumulation hinders tissue renewal and repair (Campisi, 2005). If senescence removes damaged cells, SASPs could harm remaining healthy cells. In essence, while senescence effectively suppresses tumorigenesis, it can also adversely affect surrounding cells. Interventions like stem cell replacement are not viable due to the potential recurrence of senescence.

Discussion

Zombie cells truly embody their nickname, existing without active genetic function. However, their role in tumor suppression is significant. The challenge lies in harnessing their potential for cancer-related medical advancements while mitigating their ageing effects. If the ageing aspect of SASP can be controlled, senescent cells could form the basis of groundbreaking medical treatments.

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