Senescence-associated secretory phenotype

From Wikipedia, the free encyclopedia
Jump to navigation Jump to search

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] Initially, SASP is immunosuppressive (characterized by TGF-β1 and TGF-β3) and profibrotic, but progresses to become proinflammatory (characterized by IL-1β, IL-6 and IL-8) and fibrolytic.[4][5]

SASP is heterogenous, with the exact composition dependent upon the senescent-cell inducer and the cell type.[6] Interleukin 12 (IL-12) and Interleukin 10 (IL-10) are increased more than 200-fold in replicative senescence in contrast to stress-induced senescence or proteosome-inhibited senescence where the increases are about 30-fold or less.[7] Tumor necrosis factor (TNF) is increased 32-fold in stress-induced senescence, 8-fold in replicative senescence, and only slightly in proteosome-inhibited senescence.[7] Interleukin 6 (IL-6) and interleukin 8 (IL-8) are the most conserved and robust features of SASP.[8]

An online SASP Atlas serves as a guide to the various types of SASP.[6]

SASP is one of the three main features of senescent cells, the other two features being arrested cell growth, and resistance to apoptosis.[9] SASP factors can include the anti-apoptotic protein Bcl-xL,[10] but growth arrest and SASP production are independently regulated.[11] Although SASP from senescent cells can kill neighboring normal cells, the apoptosis-resistance of senescent cells protects those cells from SASP.[12]

Causes[edit]

SASP expression is induced by a number of transcription factors, including C/EBPβ, of which the most important is NF-κB.[13][14] NF-κB is expressed as a result of inhibition of autophagy-mediated degradation of the transcription factor GATA4.[15][16] GATA4 is activated by the DNA damage response factors, which induce cellular senescence.[15] Aberrant oncogenes, DNA damage, and oxidative stress induce mitogen-activated protein kinases, which are the upstream regulators of NF-κB.[17]

mTOR (mechanistic target of rapamycin) is also a key initiator of SASP.[16] Interleukin 1 alpha (IL1A) is found on the surface of senescent cells, where it contributes to the production of SASP factors due to a positive feedback loop with NF-κB.[18][19] Translation of mRNA for IL1A is highly dependent upon mTOR activity.[20] mTOR activity increases levels of IL1A, mediated by MAPKAPK2.[18] mTOR inhibition of ZFP36L1 prevents this protein from degrading transcripts of numerous components of SASP factors.[21][22]

Ribosomal DNA (rDNA) is more vulnerable to DNA damage than DNA elsewhere in the genome such than rDNA instability can lead to cellular senescence, and thus to SASP[23] The high-mobility group proteins (HMGA) can induce senescence and SASP in a p53-dependent manner.[24]

Activation of the retrotransposon LINE1 can result in cytosolic DNA that activates the cGAS–STING cytosolic DNA sensing pathway upregulating SASP by induction of interferon type I.[24] cGAS is essential for induction of cellular senescence by DNA damage.[25]

Pathology[edit]

Senescent cells are highly metabolically active, producing large amounts of SASP, which is why senescent cells consisting of only 2% or 3% of tissue cells can be a major cause of aging-associated diseases.[22] SASP factors cause non-senescent cells to become senescent.[26] SASP factors induce insulin resistance.[27] SASP disrupts normal tissue function by producing chronic inflammation, induction of fibrosis and inhibition of stem cells.[28] Chronic inflammation associated with aging has been termed inflammaging, although SASP may be only one of the possible causes of this condition.[29] Chronic inflammation due to SASP can suppress immune system function,[3] which is one reason elderly persons are more vulnerable to COVID-19.[30]

SASP factors from senescent cells reduce nicotinamide adenine dinucleotide (NAD+) in non-senescent cells,[31] thereby reducing the capacity for DNA repair and sirtuin activity in non-senescent cells.[32] SASP induction of the NAD+ degrading enzyme CD38 on non-senescent cells may be responsible for most of this effect.[33] By contrast, NAD+ contributes to the secondary (pro-inflammatory) manifestation of SASP.[5]

SASP induces an unfolded protein response in the endoplasmic reticulum because of an accumulation of unfolded proteins, resulting in proteotoxic impairment of cell function.[34]

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.[13][28] Cancer invasiveness is promoted primarily though the actions of the SASP factors metalloproteinase, chemokine, interleukin 6 (IL-6), and interleukin 8 (IL-8).[35][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] The flavonoid apigenin has been show to strongly inhibit SASP productin.[36]

Benefits[edit]

SASP can aid in signaling to immune cells for senescent cell clearance,[37][38][39][40] with specific SASP factors secreted by senescent cells attracting and activating different components of both the innate and adaptive immune system.[38] The SASP cytokine CCL2 (MCP1) recruits macrophages to remove cancer cells.[41]

Autophagy is upregulated to promote survival.[34]

SASP factors can maintain senescent cells in their senescent state of growth arrest, thereby preventing cancerous transformation.[42]

SASP can play a beneficial role by promoting wound healing.[43] However, in contrast to the persistent character of SASP in chronic inflammation, beneficial SASP in wound healing is transitory.[43]

SASP may play a role in tissue regeneration by signaling for senescent cell clearance by immune cells, allowing progenitor cells to repopulate tissue.[44] In development, SASP also may be used to signal for senescent cell clearance to aid tissue remodeling.[45]

History[edit]

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[edit]

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. ^ a b 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. ^ 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.
  5. ^ a b Nacarelli T, Lau L, Fukumoto T, David G, Zhang R (2019). "NAD + metabolism governs the proinflammatory senescence-associated secretome". Nature Cell Biology. 21 (3): 397–407. doi:10.1038/s41556-019-0287-4. PMC 6448588. PMID 30778219.
  6. ^ a b 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.
  7. ^ a b Maciel-Barón LA, Morales-Rosales SL, Aquino-Cruz AA, Königsberg M (2016). "Senescence associated secretory phenotype profile from primary lung mice fibroblasts depends on the senescence induction stimuli". AGE. 38 (1): 26. doi:10.1007/s11357-016-9886-1. PMC 5005892. PMID 26867806.
  8. ^ Partridge L, Fuentealba M, Kennedy BK (2020). "The quest to slow ageing through drug discovery" (PDF). Nature Reviews Drug Discovery. 19 (8): 513–532. doi:10.1038/s41573-020-0067-7. PMID 32467649. S2CID 218912510.
  9. ^ 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.
  10. ^ 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.
  11. ^ 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.
  12. ^ Kirkland JL, Tchkonia T (2020). "Senolytic Drugs: From Discovery to Translation". Journal of Internal Medicine. 288 (5): 518–536. doi:10.1111/joim.13141. PMC 7405395. PMID 32686219.
  13. ^ 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.
  14. ^ 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)
  15. ^ a b 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.
  16. ^ a b Yessenkyzy A, Saliev T, Zhanaliyeva M, Nurgozhin T (2020). "Polyphenols as Caloric-Restriction Mimetics and Autophagy Inducers in Aging Research". Nutrients. 12 (5): 1344. doi:10.3390/nu12051344. PMC 7285205. PMID 32397145.
  17. ^ 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.
  18. ^ a b Laberge R, Sun Y, Orjalo AV, Patil CK, Campisi J (2015). "MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation". Nature Cell Biology. 17 (8): 1049–1061. doi:10.1038/ncb3195. PMC 4691706. PMID 26147250.
  19. ^ Wang R, Yu Z, Sunchu B, Perez VI (2017). "Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism". Aging Cell. 16 (3): 564–574. doi:10.1111/acel.12587. PMC 5418203. PMID 28371119.
  20. ^ Wang R, Sunchu B, Perez VI (2017). "Rapamycin and the inhibition of the secretory phenotype". Experimental Gerontology. 94: 89–92. doi:10.1016/j.exger.2017.01.026. PMID 28167236. S2CID 4960885.
  21. ^ Weichhart T (2018). "mTOR as Regulator of Lifespan, Aging, and Cellular Senescence: A Mini-Review". Gerontology. 84 (2): 127–134. doi:10.1159/000484629. PMC 6089343. PMID 29190625.
  22. ^ a b Papadopoli D, Boulay K, Kazak L, Hulea L (2019). "mTOR as a central regulator of lifespan and aging". F1000Research. 8: 998. doi:10.12688/f1000research.17196.1. PMC 6611156. PMID 31316753.
  23. ^ Paredes S, Angulo-Ibanez M, Tasselli L, Chua KF (2018). "The epigenetic regulator SIRT7 guards against mammalian cellular senescence induced by ribosomal DNA instability". Journal of Biological Chemistry. 293 (28): 11242–11250. doi:10.1074/jbc.AC118.003325. PMC 6052228. PMID 29728458.
  24. ^ a b Huda N, Liu G, Hong H, Yin X (2019). "Hepatic senescence, the good and the bad". World Journal of Gastroenterology. 25 (34): 5069–5081. doi:10.3748/wjg.v25.i34.5069. PMC 6747293. PMID 31558857.
  25. ^ Yang H, Wang H, Ren J, Chen ZJ (2017). "cGAS is essential for cellular senescence". Proceedings of the National Academy of Sciences of the United States of America. 114 (23): E4612–E4620. doi:10.1073/pnas.1705499114. PMC 5468617. PMID 28533362.
  26. ^ Houssaini A, Breau M, Kebe K, Adnot S (2018). "mTOR pathway activation drives lung cell senescence and emphysema". JCI Insight. 3 (3): e93203. doi:10.1172/jci.insight.93203. PMC 5821218. PMID 29415880.
  27. ^ 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.
  28. ^ a b 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.
  29. ^ Franceschi C, Campisi J (2014). "Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases". The Journals of Gerontology: Series A. 69 (Supp 1): s4–s9. doi:10.1093/gerona/glu057. PMID 24833586.
  30. ^ Akbar AN, Gilroy DW (2020). "Aging immunity may exacerbate COVID-19". Science. 369 (6501): 256–257. doi:10.1126/science.abb0762. PMID 32675364.
  31. ^ 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.
  32. ^ 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. S2CID 27313960.
  33. ^ Sabbatinelli J, Prattichizzo F, Olivieri F, Giuliani A (2019). "Where Metabolism Meets Senescence: Focus on Endothelial Cells". Frontiers in Physiology. 10: 1523. doi:10.3389/fphys.2019.01523. PMC 6930181. PMID 31920721.
  34. ^ a b 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.
  35. ^ Kim YH, Park TJ (2019). "Cellular senescence in cancer". BMB Reports. 52 (1): 42–46. doi:10.5483/BMBRep.2019.52.1.295. PMC 6386235. PMID 30526772.
  36. ^ Lim H, Heo MY, Kim HP (2019). "Flavonoids: Broad Spectrum Agents on Chronic Inflammation". Biomolecules & Therapeutics. 27 (3): 241–253. doi:10.4062/biomolther.2019.034. PMC 6513185. PMID 31006180.
  37. ^ 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.
  38. ^ a b 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. S2CID 2775067.
  39. ^ 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.
  40. ^ 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.
  41. ^ Alexander E, Hildebrand DG, Schulze-Osthoff K, Essmann F (2013). "IκBζ is a regulator of the senescence-associated secretory phenotype in DNA damage- and oncogene-induced senescence". Journal of Cell Science. 126 (Pt 16): 3738–3745. doi:10.1242/jcs.128835. PMID 23781024.
  42. ^ Freund A, Orjalo AV, Desprez P, Campisi J (2010). "Inflammatory networks during cellular senescence: causes and consequences". Trends in Molecular Medicine. 16 (5): 238–246. doi:10.1016/j.molmed.2010.03.003. PMC 2879478. PMID 20444648.
  43. ^ 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.
  44. ^ 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. S2CID 20062510.
  45. ^ 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.