Senescence-associated secretory phenotype

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Senescence-associated secretory phenotype (SASP) is a phenotype associated with senescent cells wherein those cells secrete high levels of inflammatory cytokines, immune modulators, growth factors, and proteases.[1][2] SASP is one of the three main features of senescent cells, the other two features being arrested cell growth, and resistance to apoptosis.[3]

The concept and abbreviation of SASP originated with Judith Campisi, who first published on the subject in 2008.[1]

SASP expression is induced by a number of transcription factors, the most important of which is NF-κB.[4]

SASP disrupts normal tissue function by producing chronic inflammation, induction of fibrosis and inhibition of stem cells.[5] Chronic inflammation associated with aging has been termed inflammaging, although SASP may be only one of the possible causes of that condition.[6] SASP factors induce insulin resistance.[7]

SASP factors from senescent cells reduce nicotinamide adenine dinucleotide in non-senescent cells,[8] thereby reducing the capacity for DNA repair and sirtuin activity in the non-senescent cells.[9]

Despite the fact that cellular senescence probably evolved as means of protecting against cancer early in life, SASP promotes the development of late-life cancers.[5][4] Cancer invasiveness is promoted primarily though the actions of the SASP factors interleukin 6 (IL-6) and interleukin 8 (IL-8).[1] In fact, SASP from senescent cells is associated with many aging-associated diseases, including not only cancer, but atherosclerosis and osteoarthritis.[2] For this reason, senolytic therapy has been proposed as a generalized treatment for these and many other diseases.[2]

SASP can also play a beneficial role, however, by promoting wound healing.[10] But in contrast to the persistent character of SASP in chronic inflammation, beneficial SASP in wound healing is transitory.[10]

References[edit]

  1. ^ a b c Coppé JP, Patil CK, Rodier F, Sun Y, Muñoz DP, Goldstein J, Nelson PS, Desprez PY, Campisi J (2008). "Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor". PLOS Biology. 6 (12): 2853–2868. doi:10.1371/journal.pbio.0060301. PMC 2592359. PMID 19053174.
  2. ^ a b c Childs BG, Gluscevic M, Baker DJ, Laberge RM, Marquess D, Dananberg J, van Deursen JM (2017). "Senescent cells: an emerging target for diseases of ageing". Nature Reviews Drug Discovery. 16 (10): 718–735. doi:10.1038/nrd.2017.116. PMC 5942225. PMID 28729727.
  3. ^ Campisi J, Kapahi P, Lithgow GJ, Melov S, Newman JC, Verdin E (2019). "From discoveries in ageing research to therapeutics for healthy ageing". Nature (journal). 571 (7764): 183–192. doi:10.1038/s41586-019-1365-2. PMID 31292558.
  4. ^ a b Ghosh K, Capell BC (2016). "The Senescence-Associated Secretory Phenotype: Critical Effector in Skin Cancer and Aging". Journal of Investigative Dermatology. 136 (11): 2133–2139. doi:10.1016/j.jid.2016.06.621. PMC 5526201. PMID 27543988.
  5. ^ a b van Deursen JM (2019). "Senolytic therapies for healthy longevity". Science (journal). 364 (6441): 636–637. doi:10.1126/science.aaw1299. PMID 31097655.
  6. ^ Franceschi C, Campisi J (2014). "Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases". Journal of Gerontology: Biological Sciences. 69 (Supp 1): s4–s9. doi:10.1093/gerona/glu057. PMID 24833586.
  7. ^ Palmer AK, Gustafson B, Kirkland JL, Smith U (2019). "Cellular senescence: at the nexus between ageing and diabetes". Diabetologia. 62 (10): 1835–1841. doi:10.1007/s00125-019-4934-x. PMC 6731336. PMID 31451866.
  8. ^ Chini C, Hogan KA, Warner GM, Tarragó MG, Peclat TR, Tchkonia T, Kirkland JL, Chini E (2019). "The NADase CD38 is induced by factors secreted from senescent cells providing a potential link between senescence and age-related cellular NAD+ decline". Biochemical and Biophysical Research Communications. 513 (2): 486–493. doi:10.1016/j.bbrc.2019.03.199. PMC 6486859. PMID 30975470.
  9. ^ Eric M. Verdin (2015). "NAD⁺ in aging, metabolism, and neurodegeneration". Science (journal). 350 (6265): 1208–1213. doi:10.1126/science.aac4854. PMID 26785480.
  10. ^ a b Demaria M, Ohtani N, Youssef SA, Rodier F, Toussaint W, Mitchell JR, Laberge RM, Vijg J, Van Steeg H, Dollé ME, Hoeijmakers JH, de Bruin A, Hara E, Campisi J (2014). "An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA". Developmental Cell. 31 (6): 722–733. doi:10.1016/j.devcel.2014.11.012. PMC 4349629. PMID 25499914.