There had been deliberate research on cellular senescense; causes; responses that act as stimuli along with various signalling mechanisms and networks. The research is still in its initial stages with underlying ambiguity about events leading to cellular senescence. Numerous other stresses associated with tumor suppression, besides shortening of telomeres, have induced consequences such as senescent growth halt in vitro. These stresses includes Reactive Oxygen Species (ROS) and certain DNA lesions. Along with telomere damage, they have one thing in common which is activation of DNA Damage Response (DDR).
Hayflick, along with his colleague, comprehended cellular senescence about five decades ago. He showed that some cells such as fibroblasts in human cease to replicate or divide after certain cell cycles. These cells also showed indefinite proliferation in culture medium. These cells have limited life span in terms of replication. This phenomenon was termed as cellular or replicative senescence (sometimes also labelled as cellular or replicative aging). The number of replicative cycles that cells complete before they reach senescent stage is Hayflick limit. Many researchers found out that the events leading to senescence and its effects are more complex and requires deliberate insight.
Telomere Shortening
The limited replicative life span of certain cells is due to shortening of telomere after each replicative cycle. Telomeres are present at the end of chromatids of chromosomes. These are repetitive regions of nucleotides that helps in protection of chromosomes from damage. Replication of DNA by DNA polymerase is unidirectional and need primer for extension. The incomplete replication of the ends of a linear DNA molecule is due to this. Thus after completion of every replication cycle the DNA produced has shortened telomeres. Cells with the ability to replenish telomeric regions of DNA through reverse transcriptase have not observed this. This enzyme is present in most cancer cells, stem cells and few of somatic cells.
Genomic Damage
When DNA is severely damage, many cells undergo senescence irrespective of the damage region or genomic location. There are many prominent senescence inducers such as DNA double strand breaks (DSBs). Treatment with ionizing radiation and inhibition of topoisomerase can induce these DNA breaks. Cytotoxic chemotherapies that have a persistent damaging effect on DNA molecules can induce senescence in both tumor and normal cells. Another cause can be oxidative stress which form DNA lesions and puts cell to senescent state. Oxidative stress also causes acceleration of telomere shortening. All of these inducers cause senescence due to DNA damage or by breaking strands.
Proliferation-Associated signals and mitogens
Oncogenes Induced Senescence is another name for this. Oncogenes are genes that can give rise to tumour cells. Mitogenic signals, that may be strong or chronic, plays its part in suppression of tumourigenesis by shutting down the replication machinery of cells. This can cause cellular senescence. The example of HRASV12, an oncogenic form of H-RAS, can explain this. This gene generates chronic stimulus by activating mitogen-activated protein kinase (MAPK).
The signalling pathway induces senescence in cells having normal functioning. Many cells show senescence in case of overexpression or presence of oncogenic forms. In some cells, overexpression of growth factors such as ERBB2, action of cytokines including interferon-β and several other factors that cause mitogenic stimulation also induces senescence.
Epigenomic damage
Epigenome is the complex containing chemical compounds helps in functioning of genome. Disturbance to epigenome can also leads to cellular senescence. Global chromatin relaxation mechanisms can explain this induction of senescence. A broad acting histones such as deacetylase inhibitors which induces senescence by decreasing the amount of p16INK4a which act as tumour suppressor. These inhibitors also alleviates formation of heterochromatin associated with senescence. Some cells also elicit DNA Damage Response (DDR) due to perturbations to epigenome even when there is no apparent or physical damage to DNA molecule. For example, initiation of DDR despite of any DNA damage occurs when DDR protein ATM (ataxia-telangiectasia-mutated) is activated by deacetylase inhibitors.
Activation of tumour suppressors
Induction of cellular senescence is largely established and maintained by tumour suppression pathways involving individual or both of p16INK4a/pRB and p53/p21 pathways. Many genes such as p53/p21 and p16INK4a/pRB are involved with production of proteins that help in tumour suppression. Some stimuli cause chronic activation or overexpression of these genes. Due to this senescence is induced and growth is ceased. Several other features are also regulated by p53/p21 and p16INK4a/pRB suppressive pathways.
