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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 diploid 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 confusingly 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.[4] This results in false positives for maturing tissue macrophages and senescence-associated beta-galactosidase as well as for T-cells p16Ink4A.[2][5] Senescent cells that grow attached to a solid substrate such as glass or plastic surface assume flattened appearance becoming thinner and having greater cellular and nuclear area. After staining nuclear DNA with a fluorescent dye the cellular imaging by laser scanning cytometry reveals a dramatic decrease in intensity of the mean maximum pixel of the nuclear DNA-associated fluorescence accompanied by an increase in nuclear area; thus even a more remarkable decrease in the ratio of maximal pixel to nuclear area.[6] A Senescence Associated Secretory Phenotype (SASP) consisting of inflammatory cytokines, growth factors, and proteases is another highly characteristic feature of senescent cells.[7] 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] Healthy mice treated with senolytics have shown improved cardiac and vascular, function.[2] Removal of senescent cells in normal mice increased healthspan as well as life expectancy,[8]

The nucleus of senescent cells is characterized by senescence-associated heterochromatin foci (SAHF) and DNA segments with chromatin alterations reinforcing senescence (DNA-SCARS).[9] Senescent cells affect tumour suppression, wound healing and possibly embryonic/placental development and a pathological role in age-related diseases.[10]

The experimental elimination of senescent cells from transgenic progeroid mice[11] and non-progeroid, naturally-aged mice[12][13][14] led to greater resistance against aging-associated diseases.

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.[15] Interestingly, cellular senescence in young organisms can protect against tumors, but senescence in older organisms can actually induce tumors to spread.[16]

DNA damage response

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.[17] It has been proposed that retained DSBs are major drivers of the aging process[18] (see DNA damage theory of aging).

See also

References

  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 e 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 4748967. 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 4166529. PMID 23140366.
  4. ^ Hall BM, Balan V, Gleiberman AS, Strom E, Krasnov P, Virtuoso LP, Rydkina E, Vujcic S, Balan K, Gitlin I, Leonova K, Polinsky A, Chernova OB, Gudkov AV (2016). "Aging of mice is associated with p16(Ink4a)- and β-galactosidase-positive macrophage accumulation that can be induced in young mice by senescent cells". Aging. 8 (7): 1294–1315. doi:10.18632/aging.100991. PMC 4993332. PMID 27391570.
  5. ^ Hall BM, Balan V, Gleiberman AS, Strom E, Krasnov P, Virtuoso LP, Rydkina E, Vujcic S, Balan K, Gitlin II, Leonova KI, Consiglio CR, Gollnick SO, et al. (2017). "p16(Ink4a) and senescence-associated β-galactosidase can be induced in macrophages as part of a reversible response to physiological stimuli". Aging. 9. Albany NY: 1867–1884. doi:10.18632/aging.101268.
  6. ^ Zhao H, Halicka HD, Jorgensen E, Traganos F, Darzynkiewicz Z.(2010) New biomarkers probing the depth of cell senescence assessed by laser scanning cytometry.Cytometry A, 77A, 999-1007. doi:10.1002/cyto.a.20983. PMID 20939035
  7. ^ 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.
  8. ^ Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ, Zhong J, Saltness RA, Jeganathan KB, Verzosa GC, Pezeshki A, Khazaie K, Miller JD, van Deursen JM (2016). "Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan". Nature. 530 (7589): 184–189. doi:10.1038/nature16932. PMC 4845101. PMID 26840489.
  9. ^ 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.
  10. ^ 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.
  11. ^ Baker, D.; Wijshake, T.; Tchkonia, T.; LeBrasseur, N.; Childs, B.; van de Sluis, B.; Kirkland, J.; van Deursen, J. (10 November 2011). "Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders". Nature. 479: 232–6. doi:10.1038/nature10600. PMC 3468323. PMID 22048312.
  12. ^ Xu, M; Palmer, AK; Ding, H; Weivoda, MM; Pirtskhalava, T; White, TA; Sepe, A; Johnson, KO; Stout, MB; Giorgadze, N; Jensen, MD; LeBrasseur, NK; Tchkonia, T; Kirkland, JL (2015). "Targeting senescent cells enhances adipogenesis and metabolic function in old age". eLife. 4. doi:10.7554/eLife.12997. PMC 4758946. PMID 26687007.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  13. ^ Quick, Darren (February 3, 2016). "Clearing out damaged cells in mice extends lifespan by up to 35 percent". www.gizmag.com. Retrieved 2016-02-04.
  14. ^ Regalado, Antonio (February 3, 2016). "In New Anti-Aging Strategy, Clearing Out Old Cells Increases Life Span of Mice by 25 Percent". MIT Technology Review. Retrieved 2016-02-04.
  15. ^ Burton; Faragher (2015). "Cellular senescence: from growth arrest to immunogenic conversion". AGE. 37. doi:10.1007/s11357-015-9764-2.
  16. ^ "Cellular Senescence". biologydictionary.net. Retrieved 31 July 2017.
  17. ^ 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 5334542. PMID 28124509.
  18. ^ 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. PMID 27588601.
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