Cellular senescence

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Cellular senescence
(upper) Primary mouse embryonic fibroblast cells (MEFs) before senescence. Spindle-shaped. (lower) MEFs became senescent after passages. Cells grow larger, flatten shape and expressed senescence-associated β-galactosidase (SABG, blue areas), a marker of cellular senescence.

Cellular senescence is the phenomenon by which normal ploid cells cease to divide. In culture, fibroblasts can reach a maximum of 50 cell divisions before becoming senescent. This phenomenon is known as "replicative senescence", or the Hayflick limit.[1] Replicative senescence is the result of telomere shortening that ultimately triggers a DNA damage response. Cells can also be induced to senesce via DNA damage in response to elevated reactive oxygen species (ROS), activation of oncogenes and cell-cell fusion, independent of telomere length. As such, cellular senescence represents a change in "cell state" rather than a cell becoming "aged" as the name misleadingly suggests. Nonetheless, the number of senescent cells in tissues rises substantially during normal aging.[2]

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.[3] 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.[2]

A Senescence Associated Secretory Phenotype (SASP) consisting of inflammatory cytokines, growth factors, and proteases is another highly characteristic feature of senescent cells.[4] SASP contributes to many age-related diseases, including type 2 diabetes and atherosclerosis.[2] The damaging effects of SASP have motivated researchers to develop senolytic chemicals that would kill and eliminate senescent cells to improve health in the elderly.[2]

The nucleus of senescent cells is characterized by senescence-associated heterochromatin foci (SAHF) and DNA segments with chromatin alterations reinforcing senescence (DNA-SCARS).[5] Senescent cells affect tumour suppression, wound healing and possibly embryonic/placental development and a pathological role in age-related diseases.[6]

Moreover, cellular senescence is not observed in several 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 (as noted above) it is sometimes 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.[7]

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.[8] It has been proposed that retained DSBs are major drivers of the aging process[9] (see DNA damage theory of aging).

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References[edit]

  1. ^ Hayflick L; Moorhead PS (December 1961). "The serial cultivation of human diploid cell strains". Exp. Cell Res. 25: 585–621. doi:10.1016/0014-4827(61)90192-6. PMID 13905658. 
  2. ^ a b c d Childs BG, Durik M, Baker DJ, van Deursen JM (2015). "Cellular senescence in aging and age-related disease: from mechanisms to therapy". Nature Medicine. 21 (12): 1424–1435. doi:10.1038/nm.4000. PMC 4748967Freely accessible. PMID 26646499. 
  3. ^ Campisi, Judith (February 2013). "Aging, Cellular Senescence, and Cancer". Annual Review of Physiology. 75: 685–705. doi:10.1146/annurev-physiol-030212-183653. PMC 4166529Freely accessible. PMID 23140366. 
  4. ^ Malaquin N, Martinez A, Rodier F (2016). "Keeping the senescence secretome under control: Molecular reins on the senescence-associated secretory phenotype". EXPERIMENTAL GERONTOLOGY. 82: 39–49. doi:10.1016/j.exger.2016.05.010. PMID 27235851. 
  5. ^ Rodier, F.; Campisi, J. (14 February 2011). "Four faces of cellular senescence". The Journal of Cell Biology. 192 (4): 547–556. doi:10.1083/jcb.201009094. PMC 3044123Freely accessible. PMID 21321098. 
  6. ^ Burton, Dominick G. A.; Krizhanovsky, Valery (31 July 2014). "Physiological and pathological consequences of cellular senescence". Cellular and Molecular Life Sciences. 71 (22): 4373–4386. doi:10.1007/s00018-014-1691-3. PMC 4207941Freely accessible. PMID 25080110. 
  7. ^ Burton; Faragher (2015). "Cellular senescence: from growth arrest to immunogenic conversion". AGE. 37. doi:10.1007/s11357-015-9764-2. PMC 4365077Freely accessible. PMID 25787341. 
  8. ^ Galbiati A, Beauséjour C, d'Adda di Fagagna F (2017). "A novel single-cell method provides direct evidence of persistent DNA damage in senescent cells and aged mammalian tissues". Aging Cell. 16 (2): 422–427. doi:10.1111/acel.12573. PMC 5334542Freely accessible. PMID 28124509. 
  9. ^ White RR, Vijg J (2016). "Do DNA Double-Strand Breaks Drive Aging?". Mol. Cell. 63 (5): 729–38. doi:10.1016/j.molcel.2016.08.004. PMC 5012315Freely accessible. PMID 27588601. 

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