Cellular senescence
[1][2][3] In their experiments during the early 1960s, Leonard Hayflick and Paul Moorhead found that normal human fetal fibroblasts in culture reach a maximum of approximately 50 cell population doublings before becoming senescent.
[8] The physiological importance for cell senescence has been attributed to prevention of carcinogenesis, and more recently, aging, development, and tissue repair.
[9] Senescent cells contribute to the aging phenotype, including frailty syndrome, sarcopenia, and aging-associated diseases.
Cells can also be induced to senesce by DNA damage in response to elevated reactive oxygen species (ROS), activation of oncogenes, and cell-cell fusion.
Normally, cell senescence is reached through a combination of a variety of factors (i.e., both telomere shortening and oxidative stress).
Senescent cells display persistent DDR that appears to be resistant to endogenous DNA repair activities.
[16] Although senescent cells can no longer replicate, they remain metabolically active and 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.
However, this results in a false positive for cells that naturally have these two proteins such as maturing tissue macrophages with senescence-associated beta-galactosidase and T-cells with p16Ink4A.
[18] This phenotype consists 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.
[19] Senescent cells affect tumour suppression, wound healing and possibly embryonic/placental development and a pathological role in age-related diseases.
[27] Recently, the role of telomeres in cellular senescence has aroused general interest, especially with a view to the possible genetically adverse effects of cloning.
identified a senescent phenotype in benign lesions of the skin carrying oncogenic mutations in neurofibroma patients with a defect that specifically causes an increase in Ras.
This suggests that p53 pathway could be effectively harnessed as a therapeutic intervention to trigger senescence and ultimately mitigate tumorigenesis.
The presence of both senescence and an increase in immune activity is able to regress and limit liver carcinoma growth in this mouse model.
Without Cdk 2, retinoblastoma protein (pRB) remains in its active, hypophosphorylated form and binds to the transcription factor E2F1, an important cell cycle regulator.
Senescence-associated secretory phenotype (SASP) gene expression is induced by a number of transcription factors, including C/EBPβ, of which the most important is NF-κB.
[35] Aberrant oncogenes, DNA damage, and oxidative stress induce mitogen-activated protein kinases, which are the upstream regulators of NF-κB.
[40] Senescent cells affect tumor suppression, wound healing and possibly embryonic/placental development, and play a pathological role in age-related diseases.
[43] The removal of aggregated p16 INK 4A positive senescent cells can delay tissue dysfunction and ultimately extend life.
In the 2011 Nature paper by Baker et al. a novel transgene, INK-ATTAC, was used to inducibly eliminate p16 INK4A-positive senescent cells by action of a small molecule-induced activation of caspase 8, resulting in apoptosis.
A BubR1 H/H mouse model known to experience the clinicopathological characteristics of aging-infertility, abnormal curvature to the spine, sarcopenia, cataracts, fat loss, dermal thinning, arrhythmias, etc.
[59] Other markers register morphology changes, reorganization of chromatin, apoptosis resistance, altered metabolism, enlarged cytoplasm or abnormal shape of the nucleus.
[13] This has motivated researchers to develop senolytic drugs to kill and eliminate senescent cells to improve health in the elderly.
[73] 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.
[29] Cellular senescence limits fibrosis during wound closure by inducing cell cycle arrest in myofibroblasts once they have fulfilled their function.
[75] Transplantation of only a few (1 per 10,000) senescent cells into lean middle-aged mice was shown to be sufficient to induce frailty, early onset of aging-associated diseases, and premature death.
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.
How and why 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.
As such, it is becoming apparent that senescent cells undergo conversion to an immunologic phenotype that enables them to be eliminated by the immune system.
Bottom : MEFs became senescent after passages. Cells grow larger, flatten shape and expressed senescence-associated β-galactosidase (SABG, blue areas), a marker of cellular senescence.