Skip to main content
Springer Nature Link
Log in

The Pivotal Role of Senescence in Cell Death and Aging: Where Do We Stand?

  • Molecular Biology of Cell Death and Aging (N Razdan and N Muhammad, Section Editors)
  • Published:
Current Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

See More

Cellular senescence acts as a brake pedal of the car in our system to avert accidents like cancer. Recent studies provide the lines of evidence that support how senescence contributes towards aging and age-associated diseases. How senescence plays a pivotal role in aging and cell death and their inter-relation have been discussed in detail.

Recent Findings

The current research or advancement in the field of senescence is the emergence of senolytic drugs for the eradication of senescent cells and induction of senescence in HIV-infected patients due to HAART drugs.

Summary

Senescence plays a significant role in aging and cell death as well as shows resistance to apoptosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+
from $39.99 /Month
  • Starting from 10 chapters or articles per month
  • Access and download chapters and articles from more than 300k books and 2,500 journals
  • Cancel anytime
View plans

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Explore related subjects

Discover the latest articles, books and news in related subjects, suggested using machine learning.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Alcorta DA, et al. Involvement of the cyclin dependent kinase inhibitor p16INK4a in replicative senescence of normal human fibroblasts. Proc Natl Acad Sci U S A. 1996;93:13742-7. https://doi.org/10.1073/pnas.93.24.13742.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ashcroft M, Taya Y, Vousden KH. Stress signals utilize multiple pathways to stabilize p53. Mol Cell Biol. 2000;20:3224-33. https://doi.org/10.1128/mcb.20.9.3224-3233.2000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Ayrapetov MK, et al. DNA double-strand breaks promote methylation of histone H3 on lysine 9 and transient formation of repressive chromatin. Proc Natl Acad Sci. 2014;111:9169-74. https://doi.org/10.1073/pnas.1403565111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Azmi AS, Wang Z, Philip PA, Mohammad RM, et al. Emerging Bcl-2 inhibitors for the treatment of cancer. Expert Opin. Emerg. Drugs. 2011;16:59-70. https://doi.org/10.1517/14728214.2010.515210.

    Article  CAS  Google Scholar 

  5. Baker D, Childs B, Durik M, Wijers M, et al. Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature. 2016;530:184-9. https://doi.org/10.1038/nature16932.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Beaupere C, Garcia M, Larghero J, Feve B, et al. The HIV proteins Tat and Nef promote human bone marrow mesenchymal stem cell senescence and alter osteoblastic differentiation. Aging Cell. 2015;14:534-46. https://doi.org/10.1111/acel.12308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Beausejour CM, Krtolica A, Galimi F, Narita M, et al. Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO J. 2003;22:4212-22. https://doi.org/10.1093/emboj/cdg417.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bennett GC, Baker DJ, Kirkland JL, Campisi J, et al. Senescence and apoptosis: dueling or complementary cell fates. EMBO Rep. 2014;15:1139-53. https://doi.org/10.15252/embr.201439245.

    Article  CAS  Google Scholar 

  9. Bergsbaken T, Fink SL, Cookson BT. Pyroptosis: host cell death and inflammation. Nat Rev Microbiol. 2009;7:99-109. https://doi.org/10.1038/nrmicro2070.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Berry DC, Jiang Y, Arpke RW, Close EL, et al. Cellular aging contributes to failure of cold-induced beige adipocyte formation in old mice and humans. Cell Metab. 2017;25:166-81. https://doi.org/10.1016/j.cmet.2016.10.023.

    Article  CAS  PubMed  Google Scholar 

  11. Bhattacharya S, Muhammad N, Steele R, Peng G, Ray R. Immunomodulatory role of bitter melon extract in inhibition of head and neck squamous cell carcinoma growth. Oncotarget. 2016;7(22). https://doi.org/10.18632/oncotarget.8898.

  12. Bhattacharya S, Muhammad N, Steele R, Kornbluth J, Ray R. Bitter melon enhances natural killer-mediated toxicity against head and neck cancer cells. Cancer Prev Res. 2017;10(6):337-44. https://doi.org/10.1158/1940-6207.CAPR-17-0046.

    Article  CAS  Google Scholar 

  13. Blasiak J. Senescence in the pathogenesis of age-related macular degeneration. Cell Mol Life Sci. 2020;77:789-805. https://doi.org/10.1007/s00018-019-03420-x.

    Article  CAS  PubMed  Google Scholar 

  14. Briz V, Poveda E, Soriano V. HIV entry inhibitors: mechanisms of action and resistance pathways. J Antimicrob Chemother. 2006;57:619-27. https://doi.org/10.1093/jac/dkl027.

    Article  CAS  PubMed  Google Scholar 

  15. Burd C, Sorrentino J, Clark K, Darr D, et al. Monitoring tumorigenesis and senescence in vivo with a p16INK4a-luciferase model. Cell. 2013;152:340-51. https://doi.org/10.1016/j.cell.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Cairns P, Polascik TJ, Eby Y, Tokino K, Califano J, Merlo A, et al. Frequency of homozygous deletion at p16/CDKN2 in primary human tumours. Nat Genet. 1995;11:210-2. https://doi.org/10.1038/ng1095-210.

    Article  CAS  PubMed  Google Scholar 

  17. Calcinotto A, Kohli J, Zagato E, Pellegrini L, Demaria M, Alimonti A. Cellular senescence: aging, cancer, and injury. Physiol Rev. 2019;99:1047-78. https://doi.org/10.1152/physrev.00020.2018.

    Article  CAS  PubMed  Google Scholar 

  18. Celeste A, Petersen S, Romanienko PJ, Fernandez-Capetillo O, Chen HT, Sedelnikova OA, et al. Genomic instability in mice lacking histone H2AX. Science. 2002;296:922-7. https://doi.org/10.1126/science.1069398.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Chang J, Wang Y, Shao L, Laberge RM, et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat Med. 2016;22:78-83. https://doi.org/10.1038/nm.4010.

    Article  CAS  PubMed  Google Scholar 

  20. Chaube B, Malvi P, Singh SV, et al. Targeting metabolic flexibility by simultaneously inhibiting respiratory complex 1 and lactate generation retards melanoma progression. Oncotarget. 2015;6(35):37281-99. https://doi.org/10.18632/oncotarget.6134.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Chen H, Gu X, Su I, Bottino R, Contreras JL, Tarakhovsky A, et al. Polycomb protein Ezh2 regulates pancreatic β-cell Ink4a/Arf expression and regeneration in streptozotocin-induced diabetes mellitus. Genes Dev. 2009;23:975-85. https://doi.org/10.1101/gad.1742509.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Childs B, Baker D, Wijshake T, Conover C, et al. Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science. 2016;354:472-7. https://doi.org/10.1126/science.aaf6659.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Chkhotua AB, Gabusi E, Altimari A, D’Errico A, Yakubovich M, Vienken J, et al. Increased expression of p16 (INK4a) and p27 (Kip1) cyclin-dependent kinase inhibitor genes in aging human kidney and chronic allograft nephropathy. Am J Kidney Dis. 2003;41:1303-13. https://doi.org/10.1016/S0272-6386(03)00363-9.

    Article  CAS  PubMed  Google Scholar 

  24. Cohen J, Torres C. HIV-associated cellular senescence: a contributor to accelerated aging. Ageing Res Rev. 2017;36:117-24. https://doi.org/10.1016/j.arr.2016.12.004**Association of HIV with senescence and aging. Demonstrating the commencement of senescence as a reaction to the stressors like HAART drugs, substance abuse and their relationship.

    Article  CAS  PubMed  Google Scholar 

  25. Cory S, Huang DC, Adams JM. The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene. 2003;22:8590-607. https://doi.org/10.1038/sj.onc.1207102.

    Article  CAS  PubMed  Google Scholar 

  26. Cosgrove BD, Gilbert PM, Porpiglia E, Mourkioti F, et al. Rejuvenation of the muscle stem cell population restores strength to injured aged muscles. Nat Med. 2014;20:255-64. https://doi.org/10.1038/nm.3464.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. D’Adda di Fagagna F. Living on a break: cellular senescence as a DNA-damage response. Nat Rev Cancer. 2008;8:512-22. https://doi.org/10.1038/nrc2440.

    Article  CAS  PubMed  Google Scholar 

  28. Demaria M, Ohtani N, Youssef S, Rodier F, et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev Cell. 2014;31:722-33. https://doi.org/10.1016/j.devcel.2014.11.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Denchi EL, de Lange T. Protection of telomeres through independent control of ATM and ATR by TRF2 and POT1. Nature. 2007;448:1068-71. https://doi.org/10.1038/nature06065.

    Article  CAS  PubMed  Google Scholar 

  30. Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, et al. A biomarker that identifies senescent human cell sinculture and in aging skin in vivo. Proc Natl Acad Sci U S A. 1995;92:9363-7. https://doi.org/10.1073/pnas.92.20.9363.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Domhnall MH, Jesus G. Senescence and aging: causes, consequences, and therapeutic avenues. J Cell Biol. 2018;217:65-77. https://doi.org/10.1083/jcb.201708092.

    Article  CAS  Google Scholar 

  32. Edinger AL, Thompson CB. Death by design: apoptosis, necrosis and autophagy. Curr Opin Cell Biol. 2004;16:663-9. https://doi.org/10.1016/j.ceb.2004.09.011.

    Article  CAS  PubMed  Google Scholar 

  33. Ellis HM, Horvitz HR. Genetic control of programmed cell death in the nematode C. elegans. Cell. 1986;44:817-29. https://doi.org/10.1016/0092-8674(86)90004-8.

    Article  CAS  PubMed  Google Scholar 

  34. Ewelina Wawryk-Gawda, Chylinska-Wrzos P, Lis-Sochocka M, Chłapek K, et al. P53 protein in proliferation, repair and apoptosis of cells. Protoplasma. 2014;251:525-33. https://doi.org/10.1007/s00709-013-0548-1.

    Article  CAS  PubMed  Google Scholar 

  35. Fumagalli M, Rossiello F, Clerici M, Barozzi S, Cittaro D, Kaplunov JM, et al. Telomeric DNA damage is irreparable and causes persistent DNA-damage- response activation. Nat Cell Biol. 2012;14:355-65. https://doi.org/10.1038/ncb2466.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ghobrial IM, Witzig TE, Adjei AA. Targeting apoptosis pathways in cancer therapy. CA Cancer J Clin. 2005;55:178-94. https://doi.org/10.3322/canjclin.55.3.178.

    Article  PubMed  Google Scholar 

  37. Green DR, Llambi F. Cell death signaling. Cold Spring Harb Perspect Biol. 2015;1:7. https://doi.org/10.1101/cshperspect.a006080.

    Article  CAS  Google Scholar 

  38. Haupt Y, Maya R, Kaza A, Oren M. Mdm2 promotes the rapid degradation of p53. Nature. 1997;387:296-9. https://doi.org/10.1038/387296a0**Mechanisms of cellular senescence, how it is induced and its phases. Contains information pivotal to improve the recognition and characterization of senescent cells.

    Article  CAS  PubMed  Google Scholar 

  39. Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res. 1961;25:585-621. https://doi.org/10.1016/0014-4827(61)90192-6.

    Article  CAS  PubMed  Google Scholar 

  40. Helman A, Klochendler A, Azazmeh N, Gabai Y, Horwitz E, Anzi S, et al. p16Ink4a-induced senescence of pancreatic beta cells enhances insulin secretion. Nat Med. 2016;22:412-20. https://doi.org/10.1038/nm.4054.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Herbig U, Ferreira M, Condel L, Carey D, Sedivy JM. Cellular senescence in aging primates. Science. 2006;311:1257. https://doi.org/10.1126/science.1122446.

    Article  CAS  PubMed  Google Scholar 

  42. Herman JG, et al. Inactivation of the CDKN2/p16/ MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers. Cancer Res. 1995;55:4525-30.

    CAS  PubMed  Google Scholar 

  43. Herranz N, Gil J. Mechanisms and functions of cellular senescence. J Clin Investig. 2018;128:1238-46. https://doi.org/10.1172/JCI95148** Mechanisms of cellular senescence, how it is induced and its phases. Contains information pivotal to improve the recognition and characterization of senescent cells.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Jeck WR, Siebold AP, Sharpless NE. Review: a meta-analysis of GWAS and age-associated diseases. Aging Cell. 2012;11:727-31. https://doi.org/10.1111/j.1474-9726.2012.00871.x.

    Article  CAS  PubMed  Google Scholar 

  45. Jeon OH, Kim C, Laberge RM, Demaria M, et al. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat Med. 2017;23:775-81. https://doi.org/10.1038/nm.4324.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Jeyapalan JC, Ferreira M, Sedivy JM, Herbig U. Accumulation of senescent cells in mitotic tissue of aging primates. Mech Ageing Dev. 2007;128:36-44. https://doi.org/10.1016/j.mad.2006.11.008.

    Article  CAS  PubMed  Google Scholar 

  47. Judith C. Aging, cellular senescence, and cancer. Annu Rev Physiol. 2013;75:685-705. https://doi.org/10.1146/annurev-physiol-030212-183653.

    Article  CAS  Google Scholar 

  48. Jun JI, Lau LF. The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing. Nat Cell Biol. 2010;12:676-85. https://doi.org/10.1038/ncb2070.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kastenhuber ER, Lowe SW. Putting p53 in context. Cell. 2017;170:1062-78. https://doi.org/10.1016/j.cell.2017.08.028.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972;26:239-57. https://doi.org/10.1038/bjc.1972.33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Khanna AK. Enhanced susceptibility of cyclin kinase inhibitor p21 knockout mice to high fat diet induced atherosclerosis. J Biomed Sci. 2009;16:66. https://doi.org/10.1186/1423-0127-16-66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kim KH, Chen CC, Monzon RI, Lau LF. Matricellular protein CCN1 promotes regression of liver fibrosis through induction of cellular senescence in hepatic myofibroblasts. Mol Cell Biol. 2013;33:2078-90. https://doi.org/10.1128/MCB.00049-13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kirkland JL, Tchkonia T. Cellular senescence: a translational perspective. EBioMedicine. 2017;21:21-8. https://doi.org/10.1016/j.ebiom.2017.04.013**The review describes the resistance of senescent cells towards apoptosis due to presence of anti-apoptotic proteins - BCL-W and BCL-XL.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Krishnamurthy J, Torrice C, Ramsey MR, Kovalev GI, al-Regaiey K, Su L, et al. Sharpless NE.Ink4a/Arf expression is a biomarker of aging. J Clin Invest. 2004;114:1299-307. https://doi.org/10.1172/JCI22475.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Krishnamurthy J, Ramsey MR, Ligon KL, Torrice C, et al. Sharpless. p16INK4a induces an age-dependent decline in islet regenerative potential. Nature. 2006;443:453-7. https://doi.org/10.1038/nature05092.

    Article  CAS  PubMed  Google Scholar 

  56. Kritsilis M, V Rizou S, Koutsoudaki PN, Evangelou K, et al. Ageing, cellular senescence and neurodegenerative disease. Int J Mol Sci. 2018;27:19. https://doi.org/10.3390/ijms19102937.

    Article  CAS  Google Scholar 

  57. Krizhanovsky V, Yon M, Dickins RA, Hearn S, Simon J, Miething C, et al. Senescence of activated stellate cells limits liver fibrosis. This work shows a beneficial function (fibrosis restriction) for cellular senescence beyond tumour suppression. Cell. 2008;134:657-67. https://doi.org/10.1016/j.cell.2008.06.049.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kuyinu EL, Narayanan G, Nair LS, Laurencin CT. Animal models of osteoarthritis: classification, update, and measurement of outcomes. J Orthop Surg. 2016;11:19. https://doi.org/10.1186/s13018-016-0346-5.

    Article  Google Scholar 

  59. Lee JT, Gu W. The multiple levels of regulation by p53 ubiquitination. Cell Death Differ. 2010;17:86-9. https://doi.org/10.1038/cdd.2009.77.

    Article  CAS  PubMed  Google Scholar 

  60. Li W, He Y, Zhang R, Zheng G, et al. The curcumin analog EF24 is a novel senolytic agent. Aging (Albany NY). 2019;11:771-82. https://doi.org/10.18632/aging.101787.

    Article  CAS  Google Scholar 

  61. Liton PB, Challa P, Stinnett S, Luna C, et al. Cellular senescence in the glaucomatous outflow pathway. Exp Gerontol. 2005;40:745-8. https://doi.org/10.1016/j.exger.2005.06.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Liu Y, Sanoff HK, Cho H, Burd CE, Torrice C, Ibrahim JG, et al. Expression of p16(INK4a) in peripheral blood T-cells is a biomarker of human aging. Aging Cell. 2009;8(4):439-48. https://doi.org/10.1111/j.1474-9726.2009.00489.x.

    Article  CAS  PubMed  Google Scholar 

  63. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, et al. The hallmarks of ageing. Cell. 2013;153:1194-217. https://doi.org/10.1016/j.cell.2013.05.039.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Mark SD’A. Cell death: a review of the major forms of apoptosis, necrosis. Cell Biol Int. 2019;43:582-92. https://doi.org/10.1002/cbin.11137.

    Article  Google Scholar 

  65. Martin N, Beach D, Gil J. Ageing as developmental decay: insights from p16INK4a. Trends Mol Med. 2014;20:667-74. https://doi.org/10.1016/j.molmed.2014.09.008.

    Article  CAS  PubMed  Google Scholar 

  66. McHugh D, Gil J. Senescence and aging: causes, consequences, and therapeutic avenues. J Cell Biol. 2017;217:65-77. https://doi.org/10.1083/jcb.201708092** Role of cellular senescence in aging and age-related diseases, and review of the novel treatments associated with senescence.

    Article  CAS  PubMed  Google Scholar 

  67. Meena AS, Sharma A, Kumari R, Mohammad N, Singh SV, Bhat MK. Inherent and acquired resistance to paclitaxel in hepatocellular carcinoma: molecular events involved. PLoS One. 2013;8(4):e61524. https://doi.org/10.1371/journal.pone.0061524.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Melk A, Kittikowit W, Sandhu I, Halloran KM, et al. Cell senescence in rat kidneys in vivo increases with growth and age despite lack of telomere shortening. Kidney Int. 2003a;63:2134-43. https://doi.org/10.1046/j.1523-1755.2003.00032.x.

    Article  CAS  PubMed  Google Scholar 

  69. Melk A, Kittikowit W, Sandhu I, Halloran KM, et al. Cell senescence in rat kidneys in vivo increases with growth and age despite lack of telomere shortening. Kidney Int. 2003b;63:2134-43. https://doi.org/10.1046/j.1523-1755.2003.00032.x.

    Article  CAS  PubMed  Google Scholar 

  70. Melk A, Schmidt BM, Takeuchi O, Sawitzki B, et al. Expression of p16INK4a and other cell cycle regulator and senescence associated genes in aging human kidney. Kidney Int. 2004a;65:510-20. https://doi.org/10.1111/j.1523-1755.2004.00438.x.

    Article  CAS  PubMed  Google Scholar 

  71. Melk A, Schmidt BMW, Takeuchi O, Sawitzki B, et al. Halloran. Expression of p16INK4a and other cell cycle regulator and senescence associated genes in aging human kidney. Kidney Int. 2004b;65:510-20. https://doi.org/10.1111/j.1523-1755.2004.00438.x.

    Article  CAS  PubMed  Google Scholar 

  72. Melk A, Schmidt BMW, Takeuchi O, Sawitzki B, et al. Halloran. Expression of p16INK4a and other cell cycle regulator and senescence associated genes in aging human kidney. Kidney Int. 2004c;65:510-20. https://doi.org/10.1111/j.1523-1755.2004.00438.x.

    Article  CAS  PubMed  Google Scholar 

  73. Merino D, et al. Bcl-2, Bcl-x(L), and Bcl-w are not equivalent targets of ABT-737 and navitoclax (ABT-263) in lymphoid and leukemic cells. Blood. 2012;119:5807-16. https://doi.org/10.1182/blood-2011-12-400929.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Merlo A, et al. 5’ CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nat Med. 1995;1:686-69 2. https://doi.org/10.1038/nm0795-686.

    Article  CAS  PubMed  Google Scholar 

  75. Mikolaj O, Salmonowicz H, Gladyshev VN. Integrating cellular senescence with the concept of damage accumulation in aging: relevance for clearance of senescent cells. Aging Cell. 2019;18:e12841. https://doi.org/10.1111/acel.12841.

    Article  CAS  Google Scholar 

  76. Mohammad N, Malvi P, Meena AS, et al. Cholesterol depletion by methyl-β-cyclodextrin augments tamoxifen induced cell death by enhancing its uptake in melanoma. Mol Cancer. 2014;13:204. https://doi.org/10.1186/1476-4598-13-204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Mohammad N, Singh SV, Malvi P, Chaube B, Athavale D, et al. Strategy to enhance efficacy of doxorubicin in solid tumor cells by methyl-β-cyclodextrin: involvement of p53 and Fas receptor ligand complex. Sci Rep. 2015 Jul 7;5:11853. https://doi.org/10.1038/srep11853.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Muhammad N, Steele R, Isbell S, Philips N, Ray R. Bitter melon extract inhibits breast cancer growth in preclinical model by inducing autophagic cell death. Oncotarget. 2017;8(39). https://doi.org/10.18632/oncotarget.19887.

  79. Munoz-Espin D, Serrano M. Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol. 2014;15:482-96. https://doi.org/10.1038/nrm3823.

    Article  CAS  PubMed  Google Scholar 

  80. Munoz-Espin D, Canamero M, Maraver A, Gomez-Lopez, et al. Programmed cell senescence during mammalian embryonic development. Cell. 2013;155:1104-18. https://doi.org/10.1016/j.cell.2013.10.019.

    Article  CAS  PubMed  Google Scholar 

  81. Najm M, Akhtar M, Ahmad I, Sadaf S, Mallick M, Kausar M, et al. Mutational analysis of prohibitin - a highly conserved gene in Indian female breast cancer cases. Asian Pac J Cancer Prev. 2012;13(10):5113-7.

    Article  PubMed  Google Scholar 

  82. Najm M, Zaidi S, Siddiqui W, Husain S. Immunohistochemical expression and mutation study of prohibitin gene in Indian female breast cancer cases. Med Oncol. 2013;30(3). https://doi.org/10.1007/s12032-013-0614-8.

  83. Nalysnyk L, Cid-Ruzafa J, Rotella P, Esser D. Incidence and prevalence of idiopathic pulmonary fibrosis: review of the literature. Eur Respir Rev. 2012;21:355-61. https://doi.org/10.1183/09059180.00002512.

    Article  PubMed  Google Scholar 

  84. Nandakumar J, Cech TR. Finding the end: recruitment of telomerase to telomeres. Nat. Rev. Mol. Cell Biol. 2013;14:69-82. https://doi.org/10.1038/nrm3505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Niccoli T, Partridge L. Ageing as a risk factor for disease. Curr Biol. 2012;22:R741-52. https://doi.org/10.1016/j.cub.2012.07.024.

    Article  CAS  PubMed  Google Scholar 

  86. Nicolas H, Gil J. Mechanisms and functions of cellular senescence. J Clin Invest. 2018;128:1238-46. https://doi.org/10.1172/JCI95148.

    Article  Google Scholar 

  87. Nolan D. Metabolic complications associated with HIV protease inhibitor therapy. Drugs. 2003;63:2555-74. https://doi.org/10.2165/00003495-200363230-00001.

    Article  CAS  PubMed  Google Scholar 

  88. Nolan D, Mallal S. Complications associated with NRTI therapy: update on clinical features and possible pathogenic mechanisms. Antivir Ther. 2004;9:849-63.

    CAS  PubMed  Google Scholar 

  89. North BJ, Sinclair DA. The intersection between aging and cardiovascular disease. Circ Res. 2012;110:1097-108. https://doi.org/10.1161/CIRCRESAHA.111.246876.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Ogrodnik MS, Miwi T, Tchkonia D, Tiniakos CL, et al. Cellular senescence drives age-dependent hepatic steatosis. Nat Commun. 2017;8:15691. https://doi.org/10.1038/ncomms15691.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005;435:677-81. https://doi.org/10.1038/nature03579.

    Article  CAS  PubMed  Google Scholar 

  92. Palm W, de Lange T. How shelterin protects mammalian telomeres. Annu Rev Genet. 2008;42:301-34. https://doi.org/10.1146/annurev.genet.41.110306.130350.

    Article  CAS  PubMed  Google Scholar 

  93. Patil P, Dong Q, Wang D, Chang J, Wiley C, Demaria M, et al. Systemic clearance of p16 INK4a-positive senescent cells mitigates age-associated intervertebral disc degeneration. Aging Cell. 2019;18:e12927. https://doi.org/10.1111/acel.12927.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Pauklin S, Kristjuhan A, Maimets T, Jaks V. ARF and ATM/ATR cooperate in p53-mediated apoptosis upon oncogenic stress. Biochem Biophys Res Commun. 2005;334:386-94. https://doi.org/10.1016/j.bbrc.2005.06.097.

    Article  CAS  PubMed  Google Scholar 

  95. Price JS, Waters JG, Darrah C, Pennington C, et al. The role of chondrocyte senescence in osteoarthritis. Aging Cell. 2002;1:57-65. https://doi.org/10.1046/j.1474-9728.2002.00008.x.

    Article  CAS  PubMed  Google Scholar 

  96. Querfurth HW, LaFerla FM. Alzheimer’s disease. N Engl J Med. 2010;362:329-44. https://doi.org/10.1056/NEJMra0909142.

    Article  CAS  PubMed  Google Scholar 

  97. Raisz LG. Local and systemic factors in the pathogenesis of osteoporosis. N Engl J Med. 1988;318:818-28. https://doi.org/10.1056/NEJM198803313181305.

    Article  CAS  PubMed  Google Scholar 

  98. Ressler S, Bartkova J, Niederegger H, Bartek J, et al. p16INK4A is a robust in vivo biomarker of cellular aging in human skin. Aging Cell. 2006;5:379-89. https://doi.org/10.1111/j.1474-9726.2006.00231.x.

    Article  CAS  PubMed  Google Scholar 

  99. Reut Y, Pilpel N, Tokarsky-Amiel R, Biran A, et al. Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nat Commun. 2016;7:11190. https://doi.org/10.1038/ncomms11190.

    Article  CAS  Google Scholar 

  100. Rubbi CP, Milner J. Disruption of the nucleolus mediates stabilization of p53 in response to DNA damage and other stresses. EMBO J. 2003;22:6068-77. https://doi.org/10.1093/emboj/cdg579.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Sagiv A, Biran A, Yon M, Simon J, Lowe SW, Krizhanovsky V. Granule exocytosis mediates immune surveillance of senescent cells. Oncogene. 2013;32:1971-7. https://doi.org/10.1038/onc.2012.206.

    Article  CAS  PubMed  Google Scholar 

  102. Sara RO, Amaral JD, Rodrigues CMP. Mechanism and disease implications of necroptosis and neuronal inflammation. Cell Death Dis. 2018;5(9):903. https://doi.org/10.1038/s41419-018-0872-7.

    Article  Google Scholar 

  103. Savill J, Fadok V. Corpse clearance defines the meaning of cell death. Nature. 2000;407:784-8. https://doi.org/10.1038/35037722.

    Article  CAS  PubMed  Google Scholar 

  104. Schafer MJ, White TA, Iijima K, Haak AJ, et al. Cellular senescence mediates fibrotic pulmonary disease. Nat Commun. 2017;8:14532. https://doi.org/10.1038/ncomms14532.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Schosserer M, Grillari J, Breitenbach M. The dual role of cellular senescence in developing tumors and their response to cancer therapy. Front Oncol. 2017;7:278. https://doi.org/10.3389/fonc.2017.00278.

    Article  PubMed  PubMed Central  Google Scholar 

  106. Serrano M, Hannon GJ, Beach D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature. 1993;366:704-7. https://doi.org/10.1038/366704a0.

    Article  CAS  PubMed  Google Scholar 

  107. Serrano M, Lee HW, Chin L, Cordon-Cardo C, Beach D, DePinho RA. Role of the INK4a locus in tumor suppression and cell mortality. Cell. 1996;85:27-37. https://doi.org/10.1016/s0092-8674(00)81079-x.

    Article  CAS  PubMed  Google Scholar 

  108. Sharpless N, Sherr C. Forging a signature of in vivo senescence. Nat Rev Cancer. 2015;15:397-408. https://doi.org/10.1038/nrc3960.

    Article  CAS  PubMed  Google Scholar 

  109. Shiloh Y. The ATM-mediated DNA-damage response: taking shape. Trends Biochem Sci. 2006;31:402-10. https://doi.org/10.1016/j.tibs.2006.05.004.

    Article  CAS  PubMed  Google Scholar 

  110. Singh SV, Ajay AK, Mohammad N, Malvi P, Chaube B, Meena AS, et al. Proteasomal inhibition sensitizes cervical cancer cells to mitomycin C-induced bystander effect: the role of tumour microenvironment. Cell Death Dis. 2015 Oct;6(10):e1934. https://doi.org/10.1038/cddis.2015.292.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Sluis-Cremer N, Tachedjian G. Mechanisms of inhibition of HIV replication by non-nucleoside reverse transcriptase inhibitors. Virus Res. 2008;134:147-56. https://doi.org/10.1016/j.virusres.2008.01.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Smith RL, de Boer R, Brul S, Budovskaya Y, et al. Premature and accelerated aging: HIV or HAART? Front Genet. 2012;3:328. https://doi.org/10.3389/fgene.2012.00328.

    Article  PubMed  Google Scholar 

  113. Sousa-Victor P, Gutarra S, García-Prat L, Rodriguez-Ubreva J, Ortet L, Ruiz-Bonilla V, et al. Geriatric muscle stem cells switch reversible quiescence into senescence. Nature. 2014;506:316-21. https://doi.org/10.1038/nature13013.

    Article  CAS  PubMed  Google Scholar 

  114. Sun N, Youle RJ, Finkel T. The mitochondrial basis of aging. Mol Cell. 2016;61:654-66. https://doi.org/10.1016/j.molcel.2016.01.028.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Susan E. Apoptosis: a review of programmed cell death. Toxicol Pathol. 2007;35:495-516. https://doi.org/10.1080/01926230701320337.

    Article  CAS  Google Scholar 

  116. Takahashi A, Ohtani N, Yamakoshi K, Iida SI, Tahara H, Nakayama K, et al. Mitogenic signalling and the p16INK4a-Rb pathway cooperate to enforce irreversible cellular senescence. Nat Cell Biol. 2006;8:1291-7. https://doi.org/10.1038/ncb1491.

    Article  CAS  PubMed  Google Scholar 

  117. Takahashi A, Imai Y, Yamakoshi K, Kuninaka S, Ohtani N, Yoshimoto S, et al. DNA damage signalling triggers degradation of histone methyltransferases through APC/C Cdh1 in senescent cells. Mol Cell. 2012;45:123-31. https://doi.org/10.1016/j.molcel.2011.10.018.

    Article  CAS  PubMed  Google Scholar 

  118. Toh WS, Brittberg M, Farr J, Foldager CB, Gomoll AH, Hui JHP, et al. Cellular senescence in aging and osteoarthritis. Acta Orthop. 2016;87(363):6-14. https://doi.org/10.1080/17453674.2016.1235087.

    Article  PubMed  PubMed Central  Google Scholar 

  119. Uryga AK, Bennett MR. Ageing induced vascular smooth muscle cell senescence in atherosclerosis. J Physiol. 2016;594:2115-24. https://doi.org/10.1113/JP270923.

    Article  CAS  PubMed  Google Scholar 

  120. Van Deursen JM. The role of senescent cells in ageing. Nature. 2014;509:439-46. https://doi.org/10.1038/nature13193.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Visel A, Zhu Y, May D, Afzal V, Gong E, Attanasio C, et al. Targeted deletion of the 9p21 noncoding coronary artery disease risk interval in mice. Nature. 2010;464:409-12. https://doi.org/10.1038/nature08801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Wang E. Senescent human fibroblasts resist programmed cell death, and failure to suppress bcl2 is involved. Cancer Res. 1995;55:2284-92.

    CAS  PubMed  Google Scholar 

  123. Wang C, Jurk D, Maddick M, Nelson G, Martin-Ruiz C, von Zglinicki T. DNA damage response and cellular senescence in tissues of aging mice. Aging Cell. 2009;8:311-23. https://doi.org/10.1111/j.1474-9726.2009.00481.x.

    Article  CAS  PubMed  Google Scholar 

  124. Wang Y, Chang J, Liu X, Xuan Z, et al. Discovery of piperlongumine as a potential novel lead for the development of senolytic agents. Aging (Albany NY). 2016;8:2915. https://doi.org/10.18632/aging.101100.

    Article  CAS  Google Scholar 

  125. Wen LLQ, Fengd R, Hue G, Sune H, et al. Emerging senolytic agents derived from natural products. Mechanisms of ageing and development. 2019;181(1-6). https://doi.org/10.1016/j.mad.2019.05.001**A review on natural senolytic drugs, and their role in the removal of senescent cells.

  126. Wiemann SU, Satyanarayana A, Tsahuridu M, Tillmann HL, et al. Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis. FAS EB J. 2002;6:935-42. https://doi.org/10.1096/fj.01-0977com.

    Article  Google Scholar 

  127. William MN, Rabinovich RA, Choudhury G. Ageing and the border between health and disease. Eur Respir J. 2014;44:1332-52. https://doi.org/10.1183/09031936.00134014.

    Article  Google Scholar 

  128. Xu M, Palmer A, Ding H, Weivoda M, Pirtskhalava T, White T, et al. Targeting senescent cells enhances adipogenesis and metabolic function in old age. eLife. 2015;4:e12997. https://doi.org/10.7554/eLife.12997.

    Article  PubMed  PubMed Central  Google Scholar 

  129. Xu M, Pirtskhalava T, Farr JN, Weigand BM, Palmer AK, Weivoda MM, et al. Senolytics improve physical function and increase lifespan in old age. Nat Med. 2018;24:1246-56. https://doi.org/10.1038/s41591-018-0092-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Xuebo X, Lai Y, Hua Z-C. Apoptosis and apoptotic body: disease message and therapeutic target potentials. Biosci Rep. 2019;39:BSR20180992. https://doi.org/10.1042/BSR20180992.

    Article  Google Scholar 

  131. Yanai H, Shteinberg A, Porat Z, Budovsky A, et al. Cellular senescence-like features of lung fibroblasts derived from idiopathic pulmonary fibrosis patients. Aging (Albany NY). 2015;7:664-72. https://doi.org/10.18632/aging.100807.

    Article  CAS  Google Scholar 

  132. Yip KW, Reed JC. Bcl-2 family proteins and cancer. Oncogene. 2008;27:639 8-6406. https://doi.org/10.1038/onc.2008.307.

    Article  CAS  Google Scholar 

  133. Yousefzadeh MJ, Zhu Y, McGowan SJ, Angelini L, et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018;36:18-28. https://doi.org/10.1016/j.ebiom.2018.09.015.

    Article  PubMed  PubMed Central  Google Scholar 

  134. Zeggini E, Weedon MN, Lindgren CM, Frayling TM, et al. WellcomeTrust Case Control Consortium (WTC CC). Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science. 2007;316:1336-41. https://doi.org/10.1126/science.1142364.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Zeitlin BD, Zeitlin IJ, Nor JE. Expanding circle of inhibition: small-molecule inhibitors of Bcl-2 as anticancer cell and antiangiogenic agents. J Clin Oncol. 2008;26:4180-8. https://doi.org/10.1200/JCO.2007.15.7693.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Zhang X, Zhang S, Liu X, Wang Y, et al. Oxidation resistance 1 is a novel senolytic target. Aging Cell. 2018;17:e12780. https://doi.org/10.1111/acel.12780.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Zhu Y, Tchkonia T, Pirtskhalava T, Gower AC, Ding H, Giorgadze N, et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015;14:644-58. https://doi.org/10.1111/acel.12344.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Zou L. Single- and double-stranded DNA: building a trigger of ATR-mediated DNA damage response. Genes Dev. 2007;21:879-85. https://doi.org/10.1101/gad.1550307.

    Article  CAS  PubMed  Google Scholar 

  139. Becker T, Haferkamp S. Molecular mechanisms of cellular senescence. Senescence and Senescence-Related Disorders. 2013. https://doi.org/10.5772/54120.

  140. Hernandez-Segura A, Nehme J, Demaria M.Hallmarks of Cellular Senescence.Trends Cell Biol. 2018; 28(6):436-453. https://doi.org/10.1016/j.tcb.2018.02.001.

Download references

Author information

Authors and Affiliations

  1. Jamia Millia Islamia, New Delhi, India

    Sadaf

  2. Apeejay Stya University, Gurugram, Haryana, India

    Mohammad Zeeshan Najm, Vyas Shingatgeri, Moin Uddin, Atul Kathait, Subhabrata Kar, Ishita Jain, Pulkit Datt, Komal Komal & Anoushka Sharma

  3. Albaha University, Al-Baha, Kingdom of Saudi Arabia

    Mohammad Asrar Izhari & Md Salman Akhtar

Authors
  1. Sadaf
    View author publications

    Search author on:PubMed Google Scholar

  2. Mohammad Zeeshan Najm
    View author publications

    Search author on:PubMed Google Scholar

  3. Vyas Shingatgeri
    View author publications

    Search author on:PubMed Google Scholar

  4. Moin Uddin
    View author publications

    Search author on:PubMed Google Scholar

  5. Mohammad Asrar Izhari
    View author publications

    Search author on:PubMed Google Scholar

  6. Md Salman Akhtar
    View author publications

    Search author on:PubMed Google Scholar

  7. Atul Kathait
    View author publications

    Search author on:PubMed Google Scholar

  8. Subhabrata Kar
    View author publications

    Search author on:PubMed Google Scholar

  9. Ishita Jain
    View author publications

    Search author on:PubMed Google Scholar

  10. Pulkit Datt
    View author publications

    Search author on:PubMed Google Scholar

  11. Komal Komal
    View author publications

    Search author on:PubMed Google Scholar

  12. Anoushka Sharma
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Mohammad Zeeshan Najm.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest

Human and Animal Rights

As this is a review article, it does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Molecular Biology of Cell Death and Aging

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sadaf, Najm, M.Z., Shingatgeri, V. et al. The Pivotal Role of Senescence in Cell Death and Aging: Where Do We Stand?. Curr Mol Bio Rep 6, 91–101 (2020). https://doi.org/10.1007/s40610-020-00129-w

Download citation

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1007/s40610-020-00129-w

Keywords

Profiles

  1. Subhabrata Kar View author profile