Senescence-associated secretory phenotype

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 may also consist of exosomes and ectosomes containing enzymes, microRNA, DNA fragments, and other bioactive factors.[3] SASP is heterogenous, with the exact composition dependent upon the senescent-cell inducer and the cell type.[4] Initially, SASP is immunosuppressive and profibrotic, but progresses to become proinflammatory and fibrolytic.[5]

An online SASP Atlas serves as a guide to the various types of SASP.[4]

SASP is one of the three main features of senescent cells, the other two features being arrested cell growth, and resistance to apoptosis.[6] SASP factors can include the anti-apoptotic protein Bcl-xL,[7] but growth arrest and SASP production are independently regulated.[8] Although SASP from senescent cells can kill neighboring normal cells, the apoptosis-resistance of senescent cells protects those cells from SASP.[9]

Causes

SASP expression is induced by a number of transcription factors, including C/EBPβ, of which the most important is NF-κB.[10][11] NF-κB is expressed as a result of inhibition of autophagy-mediated degradation of the transcription factor GATA4.[12] GATA4 is activated by the DNA damage response factors, which induce cellular senescence.[12] Aberrant oncogenes, DNA damage, and oxidative stress induce mitogen-activated protein kinases, which are the upstream regulators of NF-κB.[13]

Pathology

SASP factors induce insulin resistance.[14]

SASP induces an unfolded protein response in the endoplasmic reticulum because of an accumulation of unfolded proteins, resulting in proteotoxic impairment of cell function.[15] Autophagy is upregulated to promote survival.[15]

SASP disrupts normal tissue function by producing chronic inflammation, induction of fibrosis and inhibition of stem cells.[16] Chronic inflammation associated with aging has been termed inflammaging, although SASP may be only one of the possible causes of this condition.[17] SASP factors stimulate the immune system to eliminate senescent cells.[18]

SASP factors from senescent cells reduce nicotinamide adenine dinucleotide in non-senescent cells,[19] thereby reducing the capacity for DNA repair and sirtuin activity in non-senescent cells.[20]

Despite the fact that cellular senescence likely evolved as a means of protecting against cancer early in life, SASP promotes the development of late-life cancers.[10][16] 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]

Benefits

SASP can aid in signaling to immune cells for senescent cell clearance,[21][22][23] with specific SASP factors secreted by senescent cells attracting and activating different components of both the innate and adaptive immune system.[21] But with chronic inflammation, immune system function may be suppressed.[3]

SASP can also play a beneficial role by promoting wound healing.[24] However, in contrast to the persistent character of SASP in chronic inflammation, beneficial SASP in wound healing is transitory.[24]

SASP may also play a role in tissue regeneration by signaling for senescent cell clearance by immune cells, allowing progenitor cells to repopulate tissue.[25] In development, SASP also may be used to signal for senescent cell clearance to aid tissue remodeling.[26]

History

The concept and abbreviation of SASP was first established by Judith Campisi and her group, who first published on the subject in 2008.[1]

See also

References
  1. 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. 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. Prata LG, Ovsyannikova IG, Tchkonia T, Kirkland JL (2018). "Senescent cell clearance by the immune system: Emerging therapeutic opportunities". Seminars in Immunology. 40: 101275. doi:10.1016/j.smim.2019.04.003. PMC 7061456. PMID 31088710.
  4. Basisty N, Kale A, Jeon O, Kuehnemann C, Payne T, Rao C, Holtz A, Shah S, Vagisha Sharma V, Ferrucci L, Campisi J, Schilling B (2020). "A Proteomic Atlas of Senescence-Associated Secretomes for Aging Biomarker Development". PLOS Biology. 18 (1): e3000599. doi:10.1371/journal.pbio.3000599. PMC 6964821. PMID 31945054.
  5. Ito Y, Hoare M, Narita M (2017). "Spatial and Temporal Control of Senescence". TRENDS IN CELL BIOLOGY. 27 (11): 820–832. doi:10.1016/j.tcb.2017.07.004. PMID 28822679.
  6. Campisi J, Kapahi P, Lithgow GJ, Melov S, Newman JC, Verdin E (2019). "From discoveries in ageing research to therapeutics for healthy ageing". Nature. 571 (7764): 183–192. Bibcode:2019Natur.571..183C. doi:10.1038/s41586-019-1365-2. PMC 7205183. PMID 31292558.
  7. Sundeep Khosla S, Farr JN, Tchkonia T, Kirkland JL (2020). "The role of cellular senescence in ageing and endocrine diseasee". Nature Reviews Endocrinology. 16 (5): 263–275. doi:10.1038/s41574-020-0335-y. PMC 7227781. PMID 32161396.
  8. Paez-Ribes M, González-Gualda E, Doherty GJ, Muñoz-Espín D (2019). "Targeting senescent cells in translational medicine". EMBO Molecular Medicine. 11 (12): e10234. doi:10.15252/emmm.201810234. PMC 6895604. PMID 31746100.
  9. Kirkland JL, Tchkonia T (2020). "Senolytic Drugs: From Discovery to Translation". Journal of Internal Medicine. doi:10.1111/joim.13141. PMID 32686219.
  10. 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.
  11. Ley, Klaus (2008-10-08). "Faculty Opinions recommendation of Chemokine signaling via the CXCR2 receptor reinforces senescence". doi:10.3410/f.1123221.580361. Cite journal requires |journal= (help)
  12. Kang C, Xu O, Martin TD, Li MZ, Demaria M, Aron L, Lu T, Yankner BA, Campisi J, Elledge SJ (2015). "The DNA Damage Response Induces Inflammation and Senescence by Inhibiting Autophagy of GATA4". Science. 349 (6255): aaa5612. doi:10.1126/science.aaa5612. PMC 4942138. PMID 26404840.
  13. Anerillas C, Abdelmohsen K, Gorospe M (2020). "Regulation of senescence traits by MAPKs". GeroScience. 42 (2): 397–408. doi:10.1007/s11357-020-00183-3. PMC 7205942. PMID 32300964.
  14. 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.
  15. Soto-Gamez A, Quax WJ, Demaria M (2019). "Regulation of Survival Networks in Senescent Cells: From Mechanisms to Interventions". Journal of Molecular Biology. 431 (15): 2629–2643. doi:10.1016/j.jmb.2019.05.036. PMID 31153901.
  16. van Deursen JM (2019). "Senolytic therapies for healthy longevity". Science. 364 (6441): 636–637. Bibcode:2019Sci...364..636V. doi:10.1126/science.aaw1299. PMC 6816502. PMID 31097655.
  17. 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.
  18. Katlinskaya YV, Carbone CJ, Yu Q, Fuchs SY (2015). "Type 1 interferons contribute to the clearance of senescent cell". Cancer Biology & Therapy. 16 (8): 1214–1219. doi:10.1080/15384047.2015.1056419. PMC 4622626. PMID 26046815.
  19. 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.
  20. Eric M. Verdin (2015). "NAD⁺ in aging, metabolism, and neurodegeneration". Science. 350 (6265): 1208–1213. Bibcode:2015Sci...350.1208V. doi:10.1126/science.aac4854. PMID 26785480.
  21. Sagiv A, Krizhanovsky V (2013). "Immunosurveillance of senescent cells: the bright side of the senescence program". Biogerontology. 14 (6): 617–628. doi:10.1007/s10522-013-9473-0. PMID 24114507.
  22. Thiers, B.H. (January 2008). "Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas". Yearbook of Dermatology and Dermatologic Surgery. 2008: 312–313. doi:10.1016/s0093-3619(08)70921-3. ISSN 0093-3619.
  23. Rao, Sonia G.; Jackson, James G. (November 2016). "SASP: Tumor Suppressor or Promoter? Yes!". Trends in Cancer. 2 (11): 676–687. doi:10.1016/j.trecan.2016.10.001. ISSN 2405-8033. PMID 28741506.
  24. 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.
  25. Muñoz-Espín, Daniel; Serrano, Manuel (July 2014). "Cellular senescence: from physiology to pathology". Nature Reviews Molecular Cell Biology. 15 (7): 482–496. doi:10.1038/nrm3823. ISSN 1471-0080. PMID 24954210.
  26. Muñoz-Espín, Daniel; Cañamero, Marta; Maraver, Antonio; Gómez-López, Gonzalo; Contreras, Julio; Murillo-Cuesta, Silvia; Rodríguez-Baeza, Alfonso; Varela-Nieto, Isabel; Ruberte, Jesús; Collado, Manuel; Serrano, Manuel (2013-11-21). "Programmed Cell Senescence during Mammalian Embryonic Development". Cell. 155 (5): 1104–1118. doi:10.1016/j.cell.2013.10.019. ISSN 0092-8674. PMID 24238962.
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