Biology:Senescence-associated secretory phenotype

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Short description: Phenotype of senescent cells which secrete certain substances

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, chemokines, and other bioactive factors.[3][4] Soluble urokinase plasminogen activator surface receptor is part of SASP, and has been used to identify senescent cells for senolytic therapy.[5] 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.[6][7] SASP is the primary cause of the detrimental effects of senescent cells.[4]

SASP is heterogenous, with the exact composition dependent upon the senescent-cell inducer and the cell type.[4][8] 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.[9] Tumor necrosis factor (TNF) is increased 32-fold in stress-induced senescence, 8-fold in replicative senescence, and only slightly in proteosome-inhibited senescence.[9] Interleukin 6 (IL-6) and interleukin 8 (IL-8) are the most conserved and robust features of SASP.[10]

An online SASP Atlas serves as a guide to the various types of SASP.[8]

SASP is one of the three main features of senescent cells, the other two features being arrested cell growth, and resistance to apoptosis.[11] SASP factors can include the anti-apoptotic protein Bcl-xL,[12] but growth arrest and SASP production are independently regulated.[13] Although SASP from senescent cells can kill neighboring normal cells, the apoptosis-resistance of senescent cells protects those cells from SASP.[14]

Causes

SASP expression is induced by a number of transcription factors, including C/EBPβ, of which the most important is NF-κB.[15][16] NF-κB and the enzyme CD38 are mutually activating.[17] NF-κB is expressed as a result of inhibition of autophagy-mediated degradation of the transcription factor GATA4.[18][19] GATA4 is activated by the DNA damage response factors, which induce cellular senescence.[18] SASP is both a promoter of DNA damage response and a consequence of DNA damage response, in an autocrine and paracrine manner. [20] Aberrant oncogenes, DNA damage, and oxidative stress induce mitogen-activated protein kinases, which are the upstream regulators of NF-κB.[21]

mTOR (mammalian target of rapamycin) is also a key initiator of SASP.[19][22] 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.[23][24][25] Translation of mRNA for IL1A is highly dependent upon mTOR activity.[26] mTOR activity increases levels of IL1A, mediated by MAPKAPK2.[23] mTOR inhibition of ZFP36L1 prevents this protein from degrading transcripts of numerous components of SASP factors.[27][28]

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[29] The high-mobility group proteins (HMGA) can induce senescence and SASP in a p53-dependent manner.[30]

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.[30] cGAS is essential for induction of cellular senescence by DNA damage.[31]

Pathology

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.[28] SASP factors cause non-senescent cells to become senescent.[32][33] SASP factors induce insulin resistance.[34] SASP disrupts normal tissue function by producing chronic inflammation, induction of fibrosis and inhibition of stem cells.[35] Chronic inflammation associated with aging has been termed inflammaging, although SASP may be only one of the possible causes of this condition.[36] Chronic inflammation due to SASP can suppress immune system function,[3] which is one reason elderly persons are more vulnerable to COVID-19.[37] Transforming growth factor beta family members secreted by senescent cells impede differentiation of adipocytes, leading to insulin resistance.[38]

SASP factors IL-6 and TNFα enhance T-cell apoptosis, thereby impairing the capacity of the adaptive immune system.[39]

SASP factors from senescent cells reduce nicotinamide adenine dinucleotide (NAD+) in non-senescent cells,[40] thereby reducing the capacity for DNA repair and sirtuin activity in non-senescent cells.[41] SASP induction of the NAD+ degrading enzyme CD38 on non-senescent cells may be responsible for most of this effect.[42][43] By contrast, NAD+ contributes to the secondary (pro-inflammatory) manifestation of SASP.[7]

SASP induces an unfolded protein response in the endoplasmic reticulum because of an accumulation of unfolded proteins, resulting in proteotoxic impairment of cell function.[44]

SASP can either promote or inhibit cancer, depending on the SASP composition.[32] 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.[15][35] Cancer invasiveness is promoted primarily though the actions of the SASP factors metalloproteinase, chemokine, interleukin 6 (IL-6), and interleukin 8 (IL-8).[45][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 shown to strongly inhibit SASP production.[46]

Benefits

SASP can aid in signaling to immune cells for senescent cell clearance,[47][48][49][50] with specific SASP factors secreted by senescent cells attracting and activating different components of both the innate and adaptive immune system.[48] The SASP cytokine CCL2 (MCP1) recruits macrophages to remove cancer cells.[51] Although transient expression of SASP can recruit immune system cells to eliminate cancer cells as well as senescent cells, chronic SASP promotes cancer.[52] Senescent hematopoietic stem cells produces a SASP that induces an M1 polarization of macrophages which kills the senescent cells in a p53-dependent process.[53]

Autophagy is upregulated to promote survival.[44]

SASP factors can maintain senescent cells in their senescent state of growth arrest, thereby preventing cancerous transformation.[54] Additionally, SASP secreted by cells that have become senescent because of stresses can induce senescence in adjoining cells subject to the same stresses. thereby reducing cancer risk.[22]

SASP can play a beneficial role by promoting wound healing.[55] However, in contrast to the persistent character of SASP in chronic inflammation, beneficial SASP in wound healing is transitory.[55] Similarly, temporary SASP in the liver or kidney can reduce fibrosis, but chronic SASP could lead to organ dysfunction.[56][57]

SASP may play a role in tissue regeneration by signaling for senescent cell clearance by immune cells, allowing progenitor cells to repopulate tissue.[58] In development, SASP also may be used to signal for senescent cell clearance to aid tissue remodeling.[59]

Modification

SASP has been reduced through inhibition of p38 mitogen-activated protein kinases and janus kinase.[60]

The protein hnRNP A1 (heterogeneous nuclear ribonucleoprotein A1) antagonizes cellular senescence and induction of the SASP by stabilizing Oct-4 and sirtuin 1 mRNAs.[61][62]

SASP Index

A SASP index composed of 22 SASP factors has been used to evaluate treatment outcomes of late life depression.[63] Higher SASP index scores corresponded to increased incidence of treatment failure, whereas no individual SASP factors were associated with treatment failure.[63]

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. ↑ 1.0 1.1 1.2 "Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor". PLOS Biology 6 (12): 2853–2868. 2008. doi:10.1371/journal.pbio.0060301. PMID 19053174. 
  2. ↑ 2.0 2.1 2.2 "Senescent cells: an emerging target for diseases of ageing". Nature Reviews Drug Discovery 16 (10): 718–735. 2017. doi:10.1038/nrd.2017.116. PMID 28729727. 
  3. ↑ 3.0 3.1 "Senescent cell clearance by the immune system: Emerging therapeutic opportunities". Seminars in Immunology 40: 101275. 2018. doi:10.1016/j.smim.2019.04.003. PMID 31088710. 
  4. ↑ 4.0 4.1 4.2 "Senescence and the SASP: many therapeutic avenues". Genes & Development 34 (23–24): 1565–1576. 2020. doi:10.1101/gad.343129.120. PMID 33262144. 
  5. ↑ "Senolytic CAR T cells reverse senescence-associated pathologies". Nature 583 (7814): 127–132. 2020. doi:10.1038/s41586-020-2403-9. PMID 32555459. Bibcode: 2020Natur.583..127A. 
  6. ↑ "Spatial and Temporal Control of Senescence". Trends in Cell Biology 27 (11): 820–832. 2017. doi:10.1016/j.tcb.2017.07.004. PMID 28822679. https://www.repository.cam.ac.uk/handle/1810/267419. 
  7. ↑ 7.0 7.1 "NAD + metabolism governs the proinflammatory senescence-associated secretome". Nature Cell Biology 21 (3): 397–407. 2019. doi:10.1038/s41556-019-0287-4. PMID 30778219. 
  8. ↑ 8.0 8.1 "A Proteomic Atlas of Senescence-Associated Secretomes for Aging Biomarker Development". PLOS Biology 18 (1): e3000599. 2020. doi:10.1371/journal.pbio.3000599. PMID 31945054. 
  9. ↑ 9.0 9.1 "Senescence associated secretory phenotype profile from primary lung mice fibroblasts depends on the senescence induction stimuli". AGE 38 (1): 26. 2016. doi:10.1007/s11357-016-9886-1. PMID 26867806. 
  10. ↑ "The quest to slow ageing through drug discovery". Nature Reviews Drug Discovery 19 (8): 513–532. 2020. doi:10.1038/s41573-020-0067-7. PMID 32467649. https://discovery.ucl.ac.uk/id/eprint/10101648/1/Partridge_Partridge%20NRDD-16-186%20Line%20edit%20SLPLP.pdf. 
  11. ↑ "From discoveries in ageing research to therapeutics for healthy ageing". Nature 571 (7764): 183–192. 2019. doi:10.1038/s41586-019-1365-2. PMID 31292558. Bibcode: 2019Natur.571..183C. 
  12. ↑ "The role of cellular senescence in ageing and endocrine diseasee". Nature Reviews Endocrinology 16 (5): 263–275. 2020. doi:10.1038/s41574-020-0335-y. PMID 32161396. 
  13. ↑ "Targeting senescent cells in translational medicine". EMBO Molecular Medicine 11 (12): e10234. 2019. doi:10.15252/emmm.201810234. PMID 31746100. 
  14. ↑ "Senolytic Drugs: From Discovery to Translation". Journal of Internal Medicine 288 (5): 518–536. 2020. doi:10.1111/joim.13141. PMID 32686219. 
  15. ↑ 15.0 15.1 "The Senescence-Associated Secretory Phenotype: Critical Effector in Skin Cancer and Aging". Journal of Investigative Dermatology 136 (11): 2133–2139. 2016. doi:10.1016/j.jid.2016.06.621. PMID 27543988. 
  16. ↑ "Chemokine signaling via the CXCR2 receptor reinforces senescence". Cell 133 (6): 1006–18. June 2008. doi:10.1016/j.cell.2008.03.038. PMID 18555777. 
  17. ↑ "Macrophage Immunometabolism and Inflammaging: Roles of Mitochondrial Dysfunction, Cellular Senescence, CD38, and NAD". Immunometabolism 2 (3): e200026. June 2020. doi:10.20900/immunometab20200026. PMID 32774895. 
  18. ↑ 18.0 18.1 "The DNA Damage Response Induces Inflammation and Senescence by Inhibiting Autophagy of GATA4". Science 349 (6255): aaa5612. 2015. doi:10.1126/science.aaa5612. PMID 26404840. 
  19. ↑ 19.0 19.1 "Polyphenols as Caloric-Restriction Mimetics and Autophagy Inducers in Aging Research". Nutrients 12 (5): 1344. 2020. doi:10.3390/nu12051344. PMID 32397145. 
  20. ↑ "Telomere dysfunction in ageing and age-related diseases". Nature Cell Biology 24 (2): 135-147. 2022. doi:10.1038/s41556-022-00842-x. PMID 35165420. 
  21. ↑ "Regulation of senescence traits by MAPKs". GeroScience 42 (2): 397–408. 2020. doi:10.1007/s11357-020-00183-3. PMID 32300964. 
  22. ↑ 22.0 22.1 "Mechanisms and functions of cellular senescence". Journal of Clinical Investigation 128 (4): 1238–1246. 2018. doi:10.1172/JCI95148. PMID 29608137. 
  23. ↑ 23.0 23.1 "MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation". Nature Cell Biology 17 (8): 1049–1061. 2015. doi:10.1038/ncb3195. PMID 26147250. 
  24. ↑ "Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism". Aging Cell 16 (3): 564–574. 2017. doi:10.1111/acel.12587. PMID 28371119. 
  25. ↑ "In search of nutritional anti-aging targets: TOR inhibitors, SASP modulators, and BCL-2 family suppressors". Nutrition 65: 33–38. 2019. doi:10.1016/j.nut.2019.01.020. PMID 31029919. 
  26. ↑ "Rapamycin and the inhibition of the secretory phenotype". Experimental Gerontology 94: 89–92. 2017. doi:10.1016/j.exger.2017.01.026. PMID 28167236. 
  27. ↑ Weichhart T (2018). "mTOR as Regulator of Lifespan, Aging, and Cellular Senescence: A Mini-Review". Gerontology 84 (2): 127–134. doi:10.1159/000484629. PMID 29190625. 
  28. ↑ 28.0 28.1 "mTOR as a central regulator of lifespan and aging". F1000Research 8: 998. 2019. doi:10.12688/f1000research.17196.1. PMID 31316753. 
  29. ↑ "The epigenetic regulator SIRT7 guards against mammalian cellular senescence induced by ribosomal DNA instability". Journal of Biological Chemistry 293 (28): 11242–11250. 2018. doi:10.1074/jbc.AC118.003325. PMID 29728458. 
  30. ↑ 30.0 30.1 "Hepatic senescence, the good and the bad". World Journal of Gastroenterology 25 (34): 5069–5081. 2019. doi:10.3748/wjg.v25.i34.5069. PMID 31558857. 
  31. ↑ "cGAS is essential for cellular senescence". Proceedings of the National Academy of Sciences of the United States of America 114 (23): E4612–E4620. 2017. doi:10.1073/pnas.1705499114. PMID 28533362. Bibcode: 2017PNAS..114E4612Y. 
  32. ↑ 32.0 32.1 "Oncogene-induced senescence: a double edged sword in cancer". Acta Pharmacologica Sinica 39 (10): 1553–1558. 2018. doi:10.1038/aps.2017.198. PMID 29620049. 
  33. ↑ "mTOR pathway activation drives lung cell senescence and emphysema". JCI Insight 3 (3): e93203. 2018. doi:10.1172/jci.insight.93203. PMID 29415880. 
  34. ↑ "Cellular senescence: at the nexus between ageing and diabetes". Diabetologia 62 (10): 1835–1841. 2019. doi:10.1007/s00125-019-4934-x. PMID 31451866. 
  35. ↑ 35.0 35.1 van Deursen JM (2019). "Senolytic therapies for healthy longevity". Science 364 (6441): 636–637. doi:10.1126/science.aaw1299. PMID 31097655. Bibcode: 2019Sci...364..636V. 
  36. ↑ "Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases". The Journals of Gerontology: Series A 69 (Supp 1): s4–s9. 2014. doi:10.1093/gerona/glu057. PMID 24833586. https://academic.oup.com/biomedgerontology/article/69/Suppl_1/S4/587037. 
  37. ↑ "Aging immunity may exacerbate COVID-19". Science 369 (6501): 256–257. 2020. doi:10.1126/science.abb0762. PMID 32675364. Bibcode: 2020Sci...369..256A. 
  38. ↑ "Aging and adipose tissue: potential interventions for diabetes and regenerative medicine". Experimental Gerontology 86: 97–105. 2016. doi:10.1016/j.exger.2016.02.013. PMID 26924669. 
  39. ↑ "SARS-CoV-2, COVID-19 and the Ageing Immune System". Nature Aging 1 (9): 769–782. 2021. doi:10.1038/s43587-021-00114-7. PMID 34746804. 
  40. ↑ "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. 2019. doi:10.1016/j.bbrc.2019.03.199. PMID 30975470. 
  41. ↑ Eric M. Verdin (2015). "NAD⁺ in aging, metabolism, and neurodegeneration". Science 350 (6265): 1208–1213. doi:10.1126/science.aac4854. PMID 26785480. Bibcode: 2015Sci...350.1208V. 
  42. ↑ "Where Metabolism Meets Senescence: Focus on Endothelial Cells". Frontiers in Physiology 10: 1523. 2019. doi:10.3389/fphys.2019.01523. PMID 31920721. 
  43. ↑ "NAD + metabolism and its roles in cellular processes during ageing". Nature Reviews Molecular Cell Biology 22 (2): 119–141. 2021. doi:10.1038/s41580-020-00313-x. PMID 33353981. 
  44. ↑ 44.0 44.1 "Regulation of Survival Networks in Senescent Cells: From Mechanisms to Interventions". Journal of Molecular Biology 431 (15): 2629–2643. 2019. doi:10.1016/j.jmb.2019.05.036. PMID 31153901. 
  45. ↑ "Cellular senescence in cancer". BMB Reports 52 (1): 42–46. 2019. doi:10.5483/BMBRep.2019.52.1.295. PMID 30526772. 
  46. ↑ "Flavonoids: Broad Spectrum Agents on Chronic Inflammation". Biomolecules & Therapeutics 27 (3): 241–253. 2019. doi:10.4062/biomolther.2019.034. PMID 31006180. PMC 6513185. https://www.biomolther.org/journal/view.html?volume=27&number=3&spage=241&year=2019. 
  47. ↑ "Type 1 interferons contribute to the clearance of senescent cell". Cancer Biology & Therapy 16 (8): 1214–1219. 2015. doi:10.1080/15384047.2015.1056419. PMID 26046815. 
  48. ↑ 48.0 48.1 "Immunosurveillance of senescent cells: the bright side of the senescence program". Biogerontology 14 (6): 617–628. 2013. doi:10.1007/s10522-013-9473-0. PMID 24114507. 
  49. ↑ 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. 
  50. ↑ 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. 
  51. ↑ "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. 2013. doi:10.1242/jcs.128835. PMID 23781024. https://jcs.biologists.org/content/126/16/3738.long. 
  52. ↑ "The Paradoxical Role of Cellular Senescence in Cancer". Frontiers in Cell and Developmental Biology 9: 722205. 2021. doi:10.3389/fcell.2021.722205. PMID 34458273. 
  53. ↑ Lujambio A (2016). "To clear, or not to clear (senescent cells)? That is the question". BioEssays 38 (Suppl 1): s56–s64. doi:10.1002/bies.201670910. PMID 27417123. 
  54. ↑ "Inflammatory networks during cellular senescence: causes and consequences". Trends in Molecular Medicine 16 (5): 238–246. 2010. doi:10.1016/j.molmed.2010.03.003. PMID 20444648. 
  55. ↑ 55.0 55.1 "An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA". Developmental Cell 31 (6): 722–733. 2014. doi:10.1016/j.devcel.2014.11.012. PMID 25499914. 
  56. ↑ "Hepatic stellate cell senescence in liver fibrosis: Characteristics, mechanisms and perspectives". Mechanisms of Ageing and Development 199: 111572. 2021. doi:10.1016/j.mad.2021.111572. ISSN 0047-6374. PMID 34536446. 
  57. ↑ "Cellular senescence in the aging and diseased kidney". Journal of Cell Communication and Signaling 12 (1): 69–82. 2018. doi:10.1007/s12079-017-0434-2. PMID 29260442. 
  58. ↑ Muñoz-Espín, Daniel; Serrano, Manuel (July 2014). "Cellular senescence: from physiology to pathology" (in en). Nature Reviews Molecular Cell Biology 15 (7): 482–496. doi:10.1038/nrm3823. ISSN 1471-0080. PMID 24954210. https://www.nature.com/articles/nrm3823. 
  59. ↑ Muñoz-Espín, Daniel; Cañamero, Marta; Maraver, Antonio; Gómez-López, Gonzalo; Contreras, Julio; Murillo-Cuesta, Silvia; Rodríguez-Baeza, Alfonso; Varela-Nieto, Isabel et al. (2013-11-21). "Programmed Cell Senescence during Mammalian Embryonic Development" (in en). Cell 155 (5): 1104–1118. doi:10.1016/j.cell.2013.10.019. ISSN 0092-8674. PMID 24238962. 
  60. ↑ "Cellular rejuvenation: molecular mechanisms and potential therapeutic interventions for diseases". Signal Transduction and Targeted Therapy 8 (1): 116. 2023. doi:10.1038/s41392-023-01343-5. PMID 36918530. 
  61. ↑ "β-hydroxybutyrate and its metabolic effects on age-associated pathology". Experimental & Molecular Medicine 52 (4): 548–555. 2020. doi:10.1038/s12276-020-0415-z. PMID 32269287. 
  62. ↑ "From bedside to battlefield: intersection of ketone body mechanisms in geroscience with military resilience". GeroScience 43 (3): 1071–1081. 2021. doi:10.1007/s11357-020-00277-y. PMID 33006708. 
  63. ↑ 63.0 63.1 "Association of Molecular Senescence Markers in Late-Life Depression With Clinical Characteristics and Treatment Outcome". JAMA Network Open 5 (6): e2219678. 2022. doi:10.1001/jamanetworkopen.2022.19678. PMID 35771573. 

For further reading

  • Han, X., Lei, Q., Xie, J., Liu, H., Li, J., Zhang, X., ... & Gou, X. (2022). Potential Regulators of the Senescence-Associated Secretory Phenotype During Senescence and Aging. The Journals of Gerontology: Series A, 77(11), 2207-2218. PMID 35524726 doi:10.1093/gerona/glac097
  • Ohtani, N. (2022). The roles and mechanisms of senescence-associated secretory phenotype (SASP): can it be controlled by senolysis?. Inflammation and Regeneration, 42(1), 1-8. PMID 35365245 PMC 8976373 doi:10.1186/s41232-022-00197-8
  • Pan, Y., Gu, Z., Lyu, Y., Yang, Y., Chung, M., Pan, X., & Cai, S. (2022). Link Between Senescence and Cell Fate: Senescence-Associated Secretory Phenotype and Its Effects on Stem Cell Fate Transition. Rejuvenation Research, 25(4), 160-172. PMID 35365245 PMC 8976373 doi:10.1186/s41232-022-00197-8
  • Park, M., Na, J., Kwak, S. Y., Park, S., Kim, H., Lee, S. J., ... & Shim, S. (2022). Zileuton Alleviates Radiation-Induced Cutaneous Ulcers via Inhibition of Senescence-Associated Secretory Phenotype in Rodents. International Journal of Molecular Sciences, 23(15), 8390. PMID 35955523 PMC 9369445 doi:10.3390/ijms23158390



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