Cellular senescence

Cellular senescence is one phenomenon by which normal cells cease to divide. In their seminal experiments from the early 1960's, 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. 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. Cellular senescence is one phenomenon by which normal cells cease to divide. In their seminal experiments from the early 1960's, 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. 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. Mechanistically, replicative senescence is triggered by a DNA damage response which results from the shortening of telomeres during each cellular division process. Cells can also be induced to senesce independent of the number of cellular divisions via DNA damage in response to elevated reactive oxygen species (ROS), activation of oncogenes and cell-cell fusion. The number of senescent cells in tissues rises substantially during normal aging. 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. 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. 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. It has been proposed that retained DSBs are major drivers of the aging process (see DNA damage theory of aging). 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. The secretome of senescent cells is very complex. The products are mainly associated with inflammation, proliferation and changes in extracellular matrix. A Senescence Associated Secretory Phenotype (SASP) consisting of inflammatory cytokines, growth factors, and proteases is another characteristic feature of senescent cells. 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. From the growth factor group, GM-CSF and VEGF serve as SASP molecules. From cellular perspective, cooperation of transcriptional factors NF-kappaB and C/EBPbeta helps to increase the level of SAPSs. Regulation of SASP is managed through transcription level, autocrine feedback loop, but most importantly by continual DDR. Proteins p53, p21, p16ink4a and Bmi-1 have been termed as main players in senescence signalling, some of them can serve as markers.