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Cellular senescence - proposed updates/additions


Cellular senescence is one phenomenon by which normal cells cease to divide. In their seminal experiments from the early 1960s, Leonard Hayflick and Paul Moorhead found out that normal human fetal fibroblasts in culture reach a maximum of approximately 50 cell population doublings before becoming senescent.[1][2][3] This phenomenon is known as "replicative senescence", or the Hayflick limit. Hayflick's discovery that normal cells are mortal overturned a 60-year-old dogma in cell biology that maintained that all cultured cells are immortal. Hayflick found that the only immortal cultured cells are cancer cells.[4] Studies have shown that cellular senescence has many manifestations including roles in development, tissue repair, and tissue degeneration.

Cellular mechanisms

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Mechanistically, replicative senescence is triggered by cellular stresses, not limited to: DNA damage, telomere uncapping, activation of oncogenes, and elevated reactive oxygen species (ROS), and cell-cell fusion. In vitro, cellular senescence can be triggered by an extended period of propagation, inadequate growth conditions, and physiological stress.[5] Cellular senescence can also be pre-programmed to play an important role in development (see Transient senescence below).

DNA damage response

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The DNA damage response (DDR) arrests cell cycle progression until damages, such as double-strand breaks (DSBs), are repaired. Senescent cells display persistent DDR foci that appear to be resistant to endogenous DNA repair activities. Such senescent cells in culture and tissues from aged mammals retain true DSBs associated with DDR markers.[6] It has been proposed that retained DSBs are major drivers of the aging process[7] (see DNA damage theory of aging).

Role of telomeres

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Telomeres are tandem repeats at the end of chromosomes that shorten during each cycle of cell division.[8] Lately, the role of telomeres in cellular senescence has aroused general interest, especially with a view to the possible genetically adverse effects of cloning. The successive shortening of the chromosomal telomeres with each cell cycle is also believed to limit the number of divisions of the cell, thus contributing to aging. There have, on the other hand, also been reports that cloning could alter the shortening of telomeres. Some cells do not age and are, therefore, described as being "biologically immortal". It is theorized by some that when it is discovered exactly what allows these cells, whether it be the result of telomere lengthening or not, to divide without limit that it will be possible to genetically alter other cells to have the same capability.

The length of the telomere strand has senescent effects; telomere shortening activates extensive alterations in alternative RNA splicing that produce senescent toxins such as progerin, which degrades the tissue and makes it more prone to failure.[9]

Role of oncogenes

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BRAFV600E and Ras are two oncogenes implicated in cellular senescence. BRAFV600E induces senescence through synthesis and secretion of IGFBP7.[10] Ras activates the [[MAPK cascade which results in increased p53 activation and p16INK4a upregulation.[11] The transition to a state of senescence due to oncogene mutations are irreversible and have been termed oncogene-induced senescence (OIS).[12]

Signaling pathways

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There are several reported signaling pathways that lead to cellular senescence including the p53 and p16Ink4a pathways.[13] Both of these pathways are activated in response to cellular stressors and lead to cell cycle inhibition. p53 activates p21 which prevents deactivates cyclin-dependent kinase 2(Cdk 2). Without Cdk 2, retinoblastoma protein (pRB) remains in it's active, hypophosphorylated form and binds to the transcription factor E2F1, an important cell cycle regulator.[5] This prevents represses the transcriptional targets of E2F1, leading to cell cycle arrest after the G1 phase.

p16Ink4a also activates pRB, but through inactivation of cyclin-dependent kinase 4 (Cdk 4) and cyclin-dependent kinase 6 (Cdk 6). p16Ink4a is responsible for the induction of premature, stress-induced senescence.[5] This is not irreversible; silencing of p16Ink4a through promotor methylation or deletion of the p16Ink4a locus allows the cell to resume the cell cycle if senescence was initiated by p16Ink4a activation.

Characteristics of senescent cells

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Although senescent cells can no longer replicate, they remain metabolically active. There is a reduction in fatty acid use, increase in glycolysis, and reactive oxygen species generation.[14]

Senescent cells commonly adopt an immunogenic phenotype consisting of a pro-inflammatory secretome, the up-regulation of immune ligands, a pro-survival response, promiscuous gene expression (pGE) and stain positive for senescence-associated β-galactosidase activity.[15] Senescence-associated beta-galactosidase, along with p16Ink4A, is regarded to be a biomarker of cellular senescence. This results in false positives for maturing tissue macrophages and senescence-associated beta-galactosidase as well as for T-cells p16Ink4A.[16]

The secretome of senescent cells is very complex. The products are mainly associated with inflammation, proliferation and changes in extracellular matrix.[17][18] A Senescence Associated Secretory Phenotype (SASP) consisting of inflammatory cytokines, growth factors, and proteases is another characteristic feature of senescent cells.[19] There are many SASP effector mechanisms either autocrine or paracrine signalling.

Considering cytokines, SASP molecules IL-6 and IL-8 are likely to enforce senescence without causing neighbour healthy cells to age, while IL-1beta is able to induce senescence in normal cells in paracrine manner. IL-1 is also dependent on cleavage by caspase-1 and so it stimulates pro-inflammatory answer.[20][21] From the growth factor group, GM-CSF and VEGF serve as SASP molecules.[22] From cellular perspective, cooperation of transcriptional factors NF-kappaB and C/EBPbeta helps to increase the level of SAPSs.[18][23]

Regulation of SASP is managed through transcription level, autocrine feedback loop, but most importantly by continual DDR.[24][25] Proteins p53, p21, p16ink4a[26] and Bmi-1 have been termed as main players in senescence signalling, some of them can serve as markers.[27]

Other markers register morphology changes, reorganization of chromatin, apoptosis resistance, altered metabolism, enlarged cytoplasm or abnormal shape of the nucleus.[28]

SASPs have distinct effects depending on the cellular context, including inflammatory or anti-inflammatory, tumor or anti-tumor effect. While considering a pro-tumor effect, they likely support already tumor-primed cells instead of shifting healthy cells into transformation.[28] Likewise, they operate as anti-tumor protector [29] by facilitating of elimination of damaged cells by phagocytes.

SASP is associated with many age-related diseases, including type 2 diabetes and atherosclerosis.[16] This has motivated researchers to develop senolytic drugs to kill and/or eliminate senescent cells to improve health in the elderly.[16] Whether or not this approach will prove effective is debatable.

The nucleus of senescent cells is characterized by senescence-associated heterochromatin foci (SAHF) and DNA segments with chromatin alterations reinforcing senescence (DNA-SCARS).[30] Senescent cells affect tumor suppression, wound healing and possibly embryonic/placental development, and play a pathological role in age-related diseases.[31]

In the nervous system, senescence has been described in astrocytes and microglia, but is less understood in neurons. [32]

Transient senescence

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It is important to recognize that cellular senescence is not inherently a negative phenomenon. During mammalian embryogenesis, programmed cellular senescence plays a role in tissue remodeling via macrophage infiltration and subsequent clearance of senescent cells.[33] A study on the mesonephros and endolymphatic sac in mice highlighted the importance of cellular senescence for eventual morphogenesis of the embryonic kidney and the inner ear, respectively.[33]

They serve to direct tissue repair and regeneration.[11] Cellular senescence limits fibrosis during would closure by inducing cell cycle arrest in myofibroblasts once they have fulfilled their function.[11] When these cells have accomplished these tasks, the immune system clears them away. This phenomenon is termed acute senescence.[12]

The negative implications of cellular senescence present themselves in the transition from acute to chronic senescence. When the immune system cannot keep up with the rate at which senescent cells are being produced, accumulation of these cells leads to a disruption in tissue homeostasis.[34]

Cellular senescence in mammalian disease

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Biomarkers of cellular senescence have been shown to accumulate in tissues of older individuals.[35] The accumulation of senescent cells in tissues of vertebrates with age is thought to contribute to the development of ageing-related diseases, including Alzheimer's disease, type 2 diabetes, and various cancers.[16][36][37] Cellular senescence reduces tissue repairing capabilities due to cell cycle arrest of progenitor cells and increase of pro-inflammatory cytokines from the SASP.[16]

Senolytic drugs

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Targeting senescent cells is a promising strategy to overcome age-related disease, simultaneous alleviate multiple comorbidities, and mitigate the effects of frailty. Removing the senescent cells by inducing apoptosis is the most straightforward option, and there are several agents that have been shown to accomplish this.[16] Some of these senolytic drugs take advantage of the senescent-cell anti-apoptotic pathways (SCAPs); knocking out expression of the proteins involved in these pathways can lead to the death of senescent cells, leaving healthy cells.[14]

Organisms lacking senescence

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Cellular senescence is not observed in some organisms, including perennial plants, sponges, corals, and lobsters. In those species where cellular senescence is observed, cells eventually become post-mitotic when they can no longer replicate themselves through the process of cellular mitosis; i.e., cells experience replicative senescence. How and why some cells become post-mitotic in some species has been the subject of much research and speculation, but it has been suggested that cellular senescence evolved as a way to prevent the onset and spread of cancer. Somatic cells that have divided many times will have accumulated DNA mutations and would therefore be in danger of becoming cancerous if cell division continued. As such, it is becoming apparent that senescent cells undergo conversion to an immunogenic phenotype that enables them to be eliminated by the immune system.[38]

See also

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References

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