Stress response and DNA damage Mechanistically, replicative senescence can be triggered by a
DNA damage response due to the shortening of
telomeres. 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). The
DNA damage response (DDR) arrests
cell cycle progression until DNA damage, such as
double-strand breaks (DSBs), is repaired. Senescent cells display persistent DDR that appears to be resistant to endogenous
DNA repair activities. The prolonged DDR activates both ATM and ATR DNA damage kinases. The phosphorylation cascade initiated by these two kinases causes the eventual
arrest of the cell cycle. Depending on the severity of the DNA damage, the cells may no longer be able to undergo repair and either go through
apoptosis or cell senescence. It has been proposed that retained DSBs are major drivers of the
aging process. Mutations in genes relating to genome maintenance have been linked with
premature aging diseases, supporting the role of cell senescence in aging. Depletion of
NAD+ can lead to DNA damage and cellular senescence in
vascular smooth muscle cells. Although senescent cells can no longer replicate, they remain metabolically active and commonly adopt an
immunogenic phenotype that enables them to be eliminated by the immune system. The 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. Two proteins, senescence-associated beta-galactosidase and
p16Ink4A, are regarded as
biomarkers of
cellular senescence. 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. Senescent cells affect tumour suppression, wound healing, and possibly embryonic/placental development, and a pathological role in age-related diseases.
Cell growth and size Cell growth plays a crucial role in cell proliferation, regulating cellular
homeostasis and cell cycle progression through dynamic changes in cell size. The enlarged cells that
are able to re-enter the cell cycle are prone to DNA damage and experience abnormalities in signaling for repair (NHEJ pathway), eventually leading to a replication failure and a permanent cell-cycle exit. Recently, 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, contributing to aging. After sufficient shortening, proteins responsible for maintaining telomere structure, such as TRF2, are displaced, resulting in the telomere being recognized as a site of a double-strand break. This induces replicative senescence. Theoretically, it is possible, upon the discovery of the exact mechanism of biological immortality, to genetically engineer cells with 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 tissue and makes it more prone to failure.
Role of oncogenes BRAFV600E and Ras are two
oncogenes implicated in cellular senescence. BRAFV600E induces senescence through synthesis and secretion of
IGFBP7. Ras activates the
MAPK cascade which results in increased p53 activation and p16INK4a upregulation. The transition to a state of senescence due to oncogene mutations are irreversible and have been termed oncogene-induced senescence (OIS). Interestingly, even after oncogenic activation of a tissue, several researchers have identified a senescent phenotype. Researchers have 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 finding has been highly reproducible in benign prostate lesions, in melanocytic lesions of UV-irradiated HGF/SF-transgenic mice, in lymphocytes and in the mammary gland from N-Ras transgenic mice, and in hyperplasias of the pituitary gland of mice with deregulated E2F activity. The key to these findings is that genetic manipulations that abrogated the senescence response led to full-blown malignancy in those carcinomas. As such, the evidence suggests senescent cells can be associated with pre-malignant stages of the tumor. Further, it has been speculated that a senescent phenotype might serve as a promising marker for staging. There are two types of senescence
in vitro. The irreversible senescence, which is mediated by INK4a/Rb and p53 pathways, and the reversible senescent phenotype, which is mediated by p53. This suggests that the p53 pathway could be effectively harnessed as a therapeutic intervention to trigger senescence and ultimately mitigate tumorigenesis. == Signaling pathways ==