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Cellular Senescence in Intervertebral Disc Aging and Degeneration

  • Intervertebral Disk Degeneration and Regeneration (MV Risbud, Section Editor)
  • Published:
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Abstract

Purpose of review

Age is a major risk factor for multiple disease pathologies, including chronic back pain, which stems from age-related degenerative changes to intervertebral disc tissue. Growing evidence suggests that the change in phenotype of disc cells to a senescent phenotype may be one of the major driving forces of age-associated disc degeneration. This review discusses the known stressors that promote development of senescence in disc tissue and the underlying molecular mechanisms disc cells adopt to enable their transition to a senescent phenotype.

Recent findings

Increased number of senescent cells has been observed with advancing age and degeneration in disc tissue. Additionally, in vitro studies have confirmed the catabolic nature of stress-induced senescent disc cells. Several factors have been shown to establish senescence via multiple different underlying mechanisms, including the NF-κB, Wnt/B-Catenin, and SIRT1 pathways.

Summary

Cellular senescence can serve as a therapeutic target to combat age-associated disc degeneration. However, whether the different stressors utilizing different signaling networks establish different kinds of senescent types in disc cells is currently unknown and warrants further investigation.

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References

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

  1. Acharyya S, et al. Interplay of IKK/NF-kappaB signaling in macrophages and myofibers promotes muscle degeneration in Duchenne muscular dystrophy. J Clin Invest. 2007;117:889–901.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Adler AS, et al. Motif module map reveals enforcement of aging by continual NF-kappaB activity. Genes Dev. 2007;21:3244–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Antoniou J, Steffen T, Nelson F, Winterbottom N, Hollander A, Poole R, et al. The human lumbar intervertebral disc: evidence for changes in the biosynthesis and denaturation of the extracellular matrix with growth, maturation, ageing, and degeneration. J Clin Invest. 1996;98(4):996–1003.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Johnson Z, SChoepflin Z, Choi H, Shapiro I, Risbud M. Eur Cell Mater. 2015;30:104–117.

  5. Bachmeier BE, Nerlich AG, Weiler C, Paesold G, Jochum M, Boos N. Analysis of tissue distribution of TNF-alpha, TNF-alpha-receptors, and the activating TNF-alpha-converting enzyme suggests activation of the TNF-alpha system in the aging intervertebral disc. Ann N Y Acad Sci. 2007;1096:44–54.

    CAS  PubMed  Google Scholar 

  6. Baeuerle PA, Henkel T. Function and activation of NF-kappa B in the immune system. Annu Rev Immunol. 1994;12:141–79.

    CAS  PubMed  Google Scholar 

  7. •• Baker D, Childs B, Durik M, Wijers M, Sieben C, Zhong J, et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011;479:232–6 One of first reports to establish causal link between senescence and age-related pathologies.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Ben-Porath I, Weinberg RA. The signals and pathways activating cellular senescence. Int J Biochem Cell Biol. 2005;37:961–76.

    CAS  PubMed  Google Scholar 

  9. Bibby SRS, Urban JPG. Effect of nutrient deprivation on the viability of intervertebral disc cells. Eur Spine J. 2004;13:695–701.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Boos N, Weissbach S, Rohrbach H, Weiler C, Spratt K, Nerlich A. Classification of age-related changes in lumbar intervertebral discs: 2002 Volvo award in basic science. Spine (Phila. Pa. 1976). 2002;27(23):2631–44.

    Google Scholar 

  11. Boutros T, Chevet E, Metrakos P. Mitogen-activated protein (MAP) kinase/MAP kinase phosphatase regulation: roles in cell growth, death, and cancer. Pharmacol Rev. 2008;60:261–310.

    CAS  PubMed  Google Scholar 

  12. Campisi J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell. 2005;120(5):513–22.

    CAS  PubMed  Google Scholar 

  13. Kuilman T, Peeper D. Senescence-messaging secretome: SMS-ing cellular stress. Nature Cancer Reviews. 2009;9:81–94.

    CAS  PubMed  Google Scholar 

  14. Campisi J. Cellular senescence: putting the paradoxes in perspective. Curr Opin Genet Dev. 2011;21(1):107–12.

    CAS  PubMed  Google Scholar 

  15. Carafa V, Nebbioso A, Altucci L. Sirtuins and disease: the road ahead. Front Pharmacol. 2012;3:4.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Cesari M, et al. Oxidative damage, platelet activation, and inflammation to predict mobility disability and mortality in older persons: results from the health aging and body composition study. J Gerontol A Biol Sci Med Sci. 2012;67A:671–6.

    CAS  PubMed Central  Google Scholar 

  17. Chang J. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat Med. 2016;22(1):78–83.

    CAS  PubMed  Google Scholar 

  18. Chen D, Xia D, Pan Z, Xu D, Zhou Y, Wu Y, et al. Metformin protects against apoptosis and senescence in nucleus pulposus cells and ameliorates disc degeneration in vivo. Cell Death Dis. 2016;7(10):e2441. A.

    Google Scholar 

  19. Clevers H. Wnt/beta-catenin signaling in development and disease. Cell. 2006;127:469–80.

    CAS  PubMed  Google Scholar 

  20. Coppé JP, et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 2008;6:2853–68.

    PubMed  Google Scholar 

  21. Coppé J, Desprez P, Krtolica A, Campisi J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010;5:99–118.

    PubMed  PubMed Central  Google Scholar 

  22. Das R. A silver tsunami invades the health of nations, https://www.forbes.com/sites/reenitadas/2015/08/11/a-silver-tsunami-invades-the-health-of-nations/#9456a8f3efd6. Accessed 3 Mar 2018.

  23. Derby R, Lee SH, Kim BJ. Discography. In: Slipman CW, Derby R, Simeone FA, Mayer TG, editors. Interventional spine: an algorithmic approach: Elsevier; 2008. p. 291–302.

  24. Dimozi A, Mavrogonatou E, Sklirou A, Kletsas D. Oxidative stress inhibits the proliferation, induces premature senescence and promotes a catabolic phenotype in human nucleus pulposus intervertebral disc cells. Eur Cell Mater. 2015;30:89–103.

    CAS  PubMed  Google Scholar 

  25. Feng C, Zhang Y, Yang M, Lan M, Liu H, Wang J, et al. The matrikine N-acetylated proline-glycine-proline induces premature senescence of nucleus pulposus cells via CXCR1-dependent ROS accumulation and DNA damage and reinforces the destructive effect of these cells on homeostasis of intervertebral discs. Biochim Biophys Acta. 2017;1863(1):220–30.

    CAS  Google Scholar 

  26. Feng C, Zhang Y, Yang M, Lan M, Liu H, Huang B, et al. Oxygen-sensing Nox4 generates genotoxic ROS to induce premature senescence of nucleus pulposus cells through MAPK and NF-κB pathways. Oxidative Med Cell Longev. 2017;2017:7426458.

    Google Scholar 

  27. Feng C, Yang M, Zhang Y, Lan M, Huang B, Liu H, et al. Cyclic mechanical tension reinforces DNA damage and activates the p53-p21-Rb pathway to induce premature senescence of nucleus pulposus cells. Int J Mol Med. 2018;41(6):3316–26.

    PubMed  PubMed Central  Google Scholar 

  28. Finkel T, Holbrook NJ. Oxidants, oxidative stress and the biology of ageing. Nature. 2000;408:239–4.

    CAS  PubMed  Google Scholar 

  29. Freund A, Patil CK, Campisi J. p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype. EMBO J. 2011;30:1536–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. • Fuhrmann-Stroissnigg H, Ling Y, Zhao J, McGowan S, Zhu Y, Robert W, et al. Identification of HSP90 inhibitors as a novel class of senolytics. Nat Commun. 2017;8(1):422 Senolytic for the purpose of disc degeneration.

    PubMed  PubMed Central  Google Scholar 

  31. Gruber HE, Norton HJ, Hanley EN Jr. Anti-apoptotic effects of IGF-1 and PDGF on human intervertebral disc cells in vitro. Spine. 2000;25:2153–7.

    CAS  PubMed  Google Scholar 

  32. Gruber H, Ingram J, Norton H, Hanley E. Senescence in cells of the aging and degenerating intervertebral disc: immunolocalization of senescence-associated beta-galactosidase in human and sand rat discs. Spine (Phila Pa 1976). 2007;32(3):321–7.

    Google Scholar 

  33. Gruber HE, Hoelscher GL, Ingram JA, Bethea S, Hanley EN. IGF-1 rescues human intervertebral annulus cells from in vitro stress-induced premature senescence. Growth Factors (Chur, Switzerland). 2008;26:220–5.

    CAS  Google Scholar 

  34. Gruber H, Ingram J, Davis D, Hanley E. Increased cell senescence is associated with decreased cell proliferation in vivo in the degenerating human annulus. Spine J. 2009;9:210–5.

    PubMed  Google Scholar 

  35. Gruber HE, Hoelscher GL, Ingram JA, Zinchenko N, Hanley EN. Senescent vs. non-senescent cells in the human annulus in vivo: cell harvest with laser capture microdissection and gene expression studies with microarray analysis. BMC Biotechnol. 2010;10:5.

    PubMed  PubMed Central  Google Scholar 

  36. Guarente L. Mitochondria--a nexus for aging, calorie restriction, and sirtuins? Cell. 2008;132:171–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Guo J, Shao M, Lu F, Jiang J, Xia X. Role of Sirt1 plays in nucleus pulposus cells and intervertebral disc degeneration. Spine (Phila Pa 1976). 2017;42(13):E757–66.

    Google Scholar 

  38. Hamamoto H, Miyamoto H, Doita M, Takada T, Nishida K, Kurosaka M. Capability of nondegenerated and degenerated discs in producing inflammatory agents with or without macrophage interaction. Spine (Phila Pa 1976). 2012;37(3):161–7.

    Google Scholar 

  39. Hasty P, Campisi J, Hoeijmakers J, van Steeg H, Vijg J. Aging and genome maintenance: lessons from the mouse? Science. 2003;299:1355–9.

    CAS  PubMed  Google Scholar 

  40. Herbig U. Cellular senescence in aging primates. Science. 2006;311(5765):1257.

    CAS  PubMed  Google Scholar 

  41. Hirvensalo M, Rantanen T, Heikkinen E. Mobility difficulties and physical activity as predictors of mortality and loss of independence in the community-living older population. J Am Geriatr Soc. 2000;48:493–8.

    CAS  PubMed  Google Scholar 

  42. Hiyama A, Sakai D, Arai F, Nakajima D, Yokoyama K, Mochida J. Effects of a glycogen synthase kinase-3beta inhibitor (LiCl) on c-myc protein in intervertebral disc cells. J Cell Biochem. 2011;112:2974–86.

    CAS  PubMed  Google Scholar 

  43. Holguin N, Aguilar R, Harland R, Bomar B, Silva M. The aging mouse partially models the aging human spine: lumbar and coccygeal disc height, composition, mechanical properties, and Wnt signaling in young and old mice. J Appl Physiol (1985). 2014;116(12):1551–60.

    CAS  Google Scholar 

  44. Hou G, Lu H, Chen M, Yao H, Zhao H. Oxidative stress participates in age-related changes in rat lumbar intervertebral discs. Arch Gerontol Geriatr. 2014;59(3):665–9.

    CAS  PubMed  Google Scholar 

  45. Huang P, Han J, Hui L. MAPK signaling in inflammation-associated cancer development. Protein Cell. 2010;1:218–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Ishihara H, Urban JP. Effects of low oxygen concentrations and metabolic inhibitors on proteoglycan and protein synthesis rates in the intervertebral disc. J Orthop Res. 1999;17:829–35.

    CAS  PubMed  Google Scholar 

  47. • Jeon OH, Kim C, Laberge R-M, Demaria M, Rathod S, Vasserot AP, et al. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat Med. 2017;23(6):775–81 Highlights possibility of therapeutics that can be developed to clear senescent cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Jeong SW, Lee JS, Kim KW. In vitro lifespan and senescence mechanisms of human nucleus pulposus chondrocytes. Spine J. 2014;14:499–504.

    PubMed  Google Scholar 

  49. Jiang L, Zhang X, Zheng X, Ru A, Ni X, Wu Y, et al. Apoptosis, senescence, and autophagy in rat nucleus pulposus cells: implications for diabetic intervertebral disc degeneration. J Orthop Res. 2013;31(5):692–702.

    CAS  PubMed  Google Scholar 

  50. Johnson WE, Stephan S, Roberts S. The influence of serum, glucose and oxygen on intervertebral disc cell growth in vitro: implications for degenerative disc disease. Arthritis Res Ther. 2008;10(2):R46.

    PubMed  PubMed Central  Google Scholar 

  51. Kalb S, Martirosyan NL, Kalani MY, Broc GG, Theodore N. Genetics of the degenerated intervertebral disc. World Neurosurg. 2012;77(3–4):491–501.

    PubMed  Google Scholar 

  52. Kang R, Li H, Rickers K, Ringgaard S, Xie L, Bünger C. Intervertebral disc degenerative changes after intradiscal injection of TNF-α in a porcine model. Eur Spine J. 2015;24(9):2010–6.

    PubMed  Google Scholar 

  53. Kauppila L, Penttilä A, Karhunen P, Lalu K, Hannikainen P. Lumbar disc degeneration and atherosclerosis of the abdominal aorta. Spine (Phila Pa 1976). 1994;19(8):923–9.

    CAS  Google Scholar 

  54. Khan AN, Jacobsen HE, Khan J, Filippi CG, Levine M, Lehman RA Jr, et al. Inflammatory biomarkers of low back pain and disc degeneration: a review. Ann N Y Acad Sci. 2017;1410(1):68–84.

    PubMed  PubMed Central  Google Scholar 

  55. Kim HJ, et al. Antioxidant α-lipoic acid inhibits osteoclast differentiation by reducing nuclear factor-κB DNA binding and prevents in vivo bone resorption induced by receptor activator of nuclear factor-κB ligand and tumor necrosis factor-α. Free Radic Biol Med. 2006;40:1483–93.

    CAS  PubMed  Google Scholar 

  56. Kong JG, Park JB, Lee D, Park EY. Effect of high glucose on stress-induced senescence of nucleus pulposus cells of adult rats. Asian Spine J. 2015;9(2):155–61.

    PubMed  PubMed Central  Google Scholar 

  57. Kyriakis JM, Avruch J. Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update. Physiol Rev. 2012;92:689–737.

    CAS  PubMed  Google Scholar 

  58. Langley E, Pearson M, Faretta M, Bauer UM, Frye RA, Minucci S, et al. Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence. EMBO J. 2002;21:2383–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Le Maitre CL, Freemont AJ, Hoyland JA. The role of interleukin-1 in the pathogenesis of human intervertebral disc degeneration. Arthritis Res Ther. 2005;7:R732–45.

    PubMed  PubMed Central  Google Scholar 

  60. Le Maitre C, Freemont A, Hoyland J. Accelerated cellular senescence in degenerate intervertebral discs: a possible role in the pathogenesis of intervertebral disc degeneration. Arthritis Res Ther. 2007;9:45.

    Google Scholar 

  61. Le Maitre C, Hoyland J, Freemont AJ. Catabolic cytokine expression in degenerate and herniated human intervertebral discs: IL-1β and TNFα expression profile. Arthritis Res Ther. 2007;9:R77.

    PubMed  PubMed Central  Google Scholar 

  62. Li P, Gan Y, Xu Y, Wang L, Ouyang B, Zhang C, et al. 17beta-estradiol attenuates TNF-α-induced premature senescence of nucleus pulposus cells through regulating the ROS/NF-κB pathway. Int J Biol Sci. 2017;13(2):145–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Lin AW, et al. Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Genes Dev. 1998;12:3008–19.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Lin SJ, Defossez PA, Guarente L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science. 2000;289:2126–8.

    CAS  PubMed  Google Scholar 

  65. Maeda S, Kokubun S. Changes with age in proteoglycan synthesis in cells cultured in vitro from the inner and outer rabbit annulus fibrosus. Responses to interleukin-1 and interleukin-1 receptor antagonist protein. Spine (Phila Pa 1976). 2000;25:166–9.

    CAS  Google Scholar 

  66. Maruyama J, Naguro I, Takeda K, Ichijo H. Stress-activated MAP kinase cascades in cellular senescence. Curr Med Chem. 2009;16:1229–35.

    CAS  PubMed  Google Scholar 

  67. Mavrogonatou E, Kletsas D. High osmolality activates the G1 and G2 cell cycle checkpoints and affects the DNA integrity of nucleus pulposus intervertebral disc cells triggering an enhanced DNA repair response. DNA Repair (Amst). 2009;8:930–43.

    CAS  Google Scholar 

  68. Melk A, Schmidt B, Takeuchi O, Sawitzki B, Rayner D, Halloran P. Expression of p16INK4a and other cell cycle regulator and senescence associated genes in aging human kidney. Kidney Int. 2004;65(2):510–20.

    CAS  PubMed  Google Scholar 

  69. Miller J, Schmatz, Schultz A. Lumbar disc degeneration: correlation with age, sex, and spine level in 600 autopsy specimens. Spine (Phila. Pa. 1976). 1988;13(2):173–8.

    CAS  Google Scholar 

  70. Muller-Lutz A, et al. Age-dependency of glycosaminoglycan content in lumbar discs: a 3T gagCEST study. J Magn Reson Imaging. 2015. https://doi.org/10.1002/jmri.24945.

    PubMed  Google Scholar 

  71. Nasto L. Genotoxic stress accelerates age-associated degenerative changes in intervertebral discs. Mech Ageing Dev. 134:35–42.

  72. Nasto LA, et al. ISSLS prize winner: inhibition of NF-κB activity ameliorates age-associated disc degeneration in a mouse model of accelerated aging. Spine (Phila Pa 1976). 2012;37:1819–25.

    Google Scholar 

  73. Nasto LA, et al. Mitochondrial-derived reactive oxygen species (ROS) play a causal role in aging-related intervertebral disc degeneration. J Orthop Res. 2013;31:1150–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Nerlich A, Schleicher E, Boos N. 1997 Volvo award winner in basic science studies. Immunohistologic markers for age-related changes of human lumbar intervertebral discs. Spine (Phila Pa 1976). 1997;22(24):2781–95.

    CAS  Google Scholar 

  75. Nerlich AG, et al. Immunomorphological analysis of RAGE receptor expression and NF-kappaB activation in tissue samples from normal and degenerated intervertebral discs of various ages. Ann N Y Acad Sci. 2007;1096:239–48.

    CAS  PubMed  Google Scholar 

  76. Ngo K, Patil P, McGowan J, Niedernhofer L, Robbins P, Kang J, et al. Senescent intervertebral disc cells exhibit perturbed matrix homeostasis phenotype. Mech Ageing Dev. 2017;166:16–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Niedernhofer LJ, Robbins PD. Signaling mechanisms involved in the response to genotoxic stress and regulating lifespan. Int J Biochem Cell Biol. 2008;40:176–80.

    CAS  PubMed  Google Scholar 

  78. Okuma M, Miyamoto K, Chujo T, Kitahara S, Masuda K. A new gene therapy approach: In vivo transfection of “naked” NF-kB decoy oligonucleotide restored disc degeneration in the rabbit annular needle puncture model. Orthopedic Research Society, translator. 2005 at < http://www.ors.org/Transactions/51/0045.pdf>.

  79. Park JS, Park JB, Park IJ, Park EY. Accelerated premature stress-induced senescence of young annulus fibrosus cells of rats by high glucose-induced oxidative stress. Int Orthop. 2014;38:1311–20.

    PubMed  PubMed Central  Google Scholar 

  80. Phillips KL, Jordan-Mahy N, Nicklin MJ, Le Maitre CL. Interleukin-1 receptor antagonist deficient mice provide insights into pathogenesis of human intervertebral disc degeneration. Ann Rheum Dis. 2013;72(11):1860–7.

    CAS  PubMed  Google Scholar 

  81. Ponnappan RK, et al. An organ culture system to model early degenerative changes of the intervertebral disc. Arthritis Res Ther. 2011;13:R171.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Purmessur D, et al. A role for TNFα in intervertebral disc degeneration: a non-recoverable catabolic shift. Biochem Biophys Res Commun. 2013;433:151–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Risbud MV, Shapiro IM. Role of cytokines in intervertebral disc degeneration: pain and disc content. Nat Rev Rheumatol. 2014;10:44–56.

    CAS  PubMed  Google Scholar 

  84. Roughley P. Biology of intervertebral disc aging and degeneration: involvement of the extracellular matrix. Spine (Phila Pa 1976). 2004;29(23):2691–9.

    Google Scholar 

  85. Sambamoorthi U, Tan X, Deb A. Multiple chronic conditions and healthcare costs among adults. Expert Rev Pharmacoecon Outcomes Res. 2015;15(5):823–32.

    PubMed  PubMed Central  Google Scholar 

  86. Scharf B, Clement CC, Yodmuang S, Urbanska AM, Suadicani SO, Aphkhazava D, et al. Age-related carbonylation of fibrocartilage structural proteins drives tissue degenerative modification. Chem Biol. 2013;20(7):922–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Setton LA, Chen J. Mechanobiology of the intervertebral disc and relevance to disc degeneration. J Bone Joint Surg Am. 2006;88(suppl 2):52–7.

    PubMed  Google Scholar 

  88. Shamji MF, et al. Proinflammatory cytokine expression profile in degenerated and herniated human intervertebral disc tissues. Arthritis Rheum. 2010;62:1974–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Shiri R, Karppinen J, Leino-Arjas P, Solovieva S, Viikari-Juntura E. The association between smoking and low back pain: a meta-analysis. Am J Med. 2010;123(1):87.e7–35.

    Google Scholar 

  90. Sivan S, Tsitron E, Wachtel E, Roughley P, Sakkee N, van der Ham F, et al. Age-related accumulation of pentosidine in aggrecan and collagen from normal and degenerate human intervertebral discs. Biochem J. 2006;399(1):29–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. The Burden of Musculoskeletal Diseases in the United States (BMUS). American Academy of Orthopaedic Surgeons. 2008. at < http://www.boneandjointburden.org/docs/TheBurden of Musculoskeletal Diseases in the United States (BMUS)1st Edition(2008).pdf>.

  92. Tissenbaum HA, Guarente L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature. 2001;410:227–30.

    CAS  PubMed  Google Scholar 

  93. Vamvakas S, Mavrogonatou E, Kletsas D. Human nucleus pulposus intervertebral disc cells becoming senescent using different treatments exhibit a similar transcriptional profile of catabolic and inflammatory genes. Eur Spine J. 2017;26(8):2063–71.

    PubMed  Google Scholar 

  94. Viollet B, et al. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond). 2012;122(6):253–70.

    CAS  Google Scholar 

  95. Vo N, et al. Accelerated aging of intervertebral discs in a mouse model of progeria. J Orthop Res. 2010;28:1600–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Vo N, Hartman R, Patil P, Risbud M, Kletsas D, Iatridis J, et al. Molecular mechanisms of biological aging in intervertebral discs. J Orthop Res. 2016;34(8):1289–306.

    PubMed  PubMed Central  Google Scholar 

  97. Wagner EF, Nebreda AR. Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer. 2009;9:537–49.

    CAS  PubMed  Google Scholar 

  98. Wang D. Spine degeneration in a murine model of chronic human tobacco smokers. Osteoarthr Cartil. 2012;20:896–905.

    CAS  Google Scholar 

  99. 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(3):311–23.

    CAS  PubMed  Google Scholar 

  100. Wang X, Zou M, Li J, Wang B, Zhang Q, Liu F, et al. LncRNA H19 targets miR-22 to modulate H2 O2 -induced deregulation in nucleus pulposus cell senescence, proliferation, and ECM synthesis through Wnt signaling. J Cell Biochem. 2018;119(6):4990–5002.

    CAS  PubMed  Google Scholar 

  101. Wiley C, Campisi J. From ancient pathways to aging cells - connecting metabolism and cellular senescence. Cell Metab. 2016;23(6):1013–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Wuertz K, Vo N, Kletsas D, Boos N. Inflammatory and catabolic signalling in intervertebral discs: the roles of NF-κB and MAP kinases. Eur Cell Mater. 2012;23:103–19.

    CAS  PubMed  Google Scholar 

  103. Xia X, Guo J, Lu F, Jiang J. SIRT1 plays a protective role in intervertebral disc degeneration in a puncture-induced rodent model. Spine. 2015;40:E515–24.

    PubMed  Google Scholar 

  104. Xing QJ, et al. Leg amputation accelerates senescence of rat lumbar intervertebral discs. Spine (Phila Pa 1976). 2010;35:E1253–61.

    Google Scholar 

  105. Yang X, Jin L, Yao L, Shen F, Shimer A, Li X. Antioxidative nanofullerol prevents intervertebral disk degeneration. Int J Nanomedicine. 2014;9:2419–30.

    PubMed  PubMed Central  Google Scholar 

  106. Yang L, Rong Z, Zeng M, Cao Y, Gong X, Lin L, et al. Pyrroloquinoline quinone protects nucleus pulposus cells from hydrogen peroxide-induced apoptosis by inhibiting the mitochondria-mediated pathway. Eur Spine J. 2015;24(8):1702–10.

    PubMed  Google Scholar 

  107. Zhou N, Lin X, Dong W, Huang W, Jiang W, Lin L, et al. SIRT1 alleviates senescence of degenerative human intervertebral disc cartilage endo-plate cells via the p53/p21 pathway. Sci Rep. 2016;6:22628.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 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(4):644–58.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank Jessa Darwin for her editorial assistance.

Funding

This work was made possible in part by the Public Health Service grants R01 AG044376-01 (NV), P01-AG043376 (LJN and PDR) and U19 AG056278 (LJN and PDR) from the National Institute of Health, the Glenn Foundation (LJN) and UPMC Department of Orthopaedic Surgery.

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Authors and Affiliations

  1. Department of Orthopedic Surgery, University of Pittsburgh, Pittsburgh, PA, USA

    Prashanti Patil, Joon Lee, Gwendolyn Sowa & Nam Vo

  2. Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota Medical School, Minneapolis, MN, USA

    Laura J. Niedernhofer & Paul D. Robbins

  3. Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, PA, USA

    Gwendolyn Sowa

  4. Ferguson Laboratory for Orthopaedic Research, University of Pittsburgh, 200 Lothrop St., E1648, Pittsburgh, PA, 15213, USA

    Nam Vo

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  1. Prashanti Patil
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  2. Laura J. Niedernhofer
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  3. Paul D. Robbins
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  4. Joon Lee
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  5. Gwendolyn Sowa
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  6. Nam Vo
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Correspondence to Nam Vo.

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Conflict of Interest

Prashanti Patil, Joon Lee, Gwendolyn Sowa, and Nam Vo each declare no potential conflicts of interest.

Laura J. Niedernhofer is an SAB member for Innate Biologics and Castle Creek and reports a patent pending.

Paul D. Robbins is an SAB member for Innate Biologics, Tissuegene, Unicyte, Engene, and Genascence and co-founder of Genascence. Dr. Robbins also reports a patent pending.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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This article is part of the Topical Collection on Intervertebral Disk Degeneration and Regeneration

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Patil, P., Niedernhofer, L.J., Robbins, P.D. et al. Cellular Senescence in Intervertebral Disc Aging and Degeneration. Curr Mol Bio Rep 4, 180–190 (2018). https://doi.org/10.1007/s40610-018-0108-8

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