Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Senescent cells: an emerging target for diseases of ageing

Key Points

  • Cellular senescence is a tumour-suppressive fate by which damaged cells permanently withdraw from the cell cycle and acquire a distinct secretome.

  • A variety of age-related diseases as well as beneficial, normal processes have been linked to either senescence arrest or to factors released in the senescent cell (SNC) secretome in recent years.

  • Evidence for a potential role of SNCs in major diseases, including osteoarthritis, atherosclerosis and cancer, has sparked interest in the development of senotherapies, treatments aimed at neutralizing the disease-causing features of SNCs.

  • One main senotherapeutic strategy is senolysis in which drugs (senolytics) are used to specifically and efficiently kill SNCs. First-generation senolytics generally act by inhibiting pro-survival adaptations that SNCs use to resist apoptosis and have shown efficacy against atherosclerosis, osteoarthritis and other age-related diseases.

  • Inhibition of the senescence-associated secretory phenotype (SASP) may be another useful senotherapy, but — in contrast to senolysis — this would likely require continuous dosing, whereas SNC killing could be carried out intermittently.

  • Senotherapy is a promising new approach to treating age-related diseases, but successfully translating this to the clinic will require new methods for evaluating SNC burden in humans, a clear mechanistic understanding of the link between senescence and disease and proof that senotherapy is safe.

Abstract

Chronological age represents the single greatest risk factor for human disease. One plausible explanation for this correlation is that mechanisms that drive ageing might also promote age-related diseases. Cellular senescence, which is a permanent state of cell cycle arrest induced by cellular stress, has recently emerged as a fundamental ageing mechanism that also contributes to diseases of late life, including cancer, atherosclerosis and osteoarthritis. Therapeutic strategies that safely interfere with the detrimental effects of cellular senescence, such as the selective elimination of senescent cells (SNCs) or the disruption of the SNC secretome, are gaining significant attention, with several programmes now nearing human clinical studies.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Timeline of milestones relevant to senotherapy.
Figure 2: Hallmarks of SNCs.
Figure 3: Preclinical testing of senolytic candidates.

References

  1. Weismann, A. Collected Essays upon Heredity and Kindred Biological Problems (ed. Poulton, E. B.) (Clarendon, 1881).

    Google Scholar 

  2. Hayflick, L. & Moorhead, P. S. The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585–621 (1961). First detection of cellular senescence in vitro.

    CAS  PubMed  Google Scholar 

  3. Campisi, J. Aging, cellular senescence, and cancer. Annu. Rev. Physiol. 75, 685–705 (2013).

    CAS  PubMed  Google Scholar 

  4. Munoz-Espin, D. & Serrano, M. Cellular senescence: from physiology to pathology. Nat. Rev. Mol. Cell Biol. 15, 482–496 (2014).

    CAS  PubMed  Google Scholar 

  5. van Deursen, J. M. The role of senescent cells in ageing. Nature 509, 439–446 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Sharpless, N. E. & Sherr, C. J. Forging a signature of in vivo senescence. Nat. Rev. Cancer 15, 397–408 (2015). This review comprehensively examined the question of SNC detection, quantification and identification in vivo , and is an excellent resource for new investigators to the field.

    CAS  PubMed  Google Scholar 

  7. Baker, D. J. et al. Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature 530, 184–189 (2016). This is a first demonstration that SNCs reduce lifespan and negatively impact healthspan in naturally-aged, non-progeroid mice.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Jeon, O. H. et al. Clearance of senescent cells prevents the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat. Med. 23, 775–781 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Baker, D. J. et al. Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency. Nat. Cell Biol. 10, 825–836 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Baker, D. J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011). Proof-of-concept study for transgene-mediated SNC killing and first demonstration that removing SNCs once they arise extends healthspan in vivo.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Childs, B. G. et al. Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science 354, 472–477 (2016). This study links the pro-inflammatory, proteolytic properties of plaque SNCs to progression and destabilization of atherosclerosis.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Munoz-Espin, D. et al. Programmed cell senescence during mammalian embryonic development. Cell 155, 1104–1118 (2013).

    CAS  PubMed  Google Scholar 

  13. Mosteiro, L. et al. Tissue damage and senescence provide critical signals for cellular reprogramming in vivo. Science 354, aaf4445 (2016).

    PubMed  Google Scholar 

  14. Storer, M. et al. Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell 155, 1119–1130 (2013). References 12 and 14 show that cellular senescence contributes to tissue patterning during mammalian embryogenesis.

    CAS  PubMed  Google Scholar 

  15. Demaria, M. et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev. Cell 31, 722–733 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Chuprin, A. et al. Cell fusion induced by ERVWE1 or measles virus causes cellular senescence. Genes Dev. 27, 2356–2366 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Li, T. et al. Tumor suppression in the absence of p53-mediated cell-cycle arrest, apoptosis, and senescence. Cell 149, 1269–1283 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Helman, A. et al. p16Ink4a-induced senescence of pancreatic beta cells enhances insulin secretion. Nat. Med. 22, 412–420 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Rudin, C. M. et al. Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer. Clin. Cancer Res. 18, 3163–3169 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Laberge, R. M. et al. MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nat. Cell Biol. 17, 1049–1061 (2015). This study provides proof of concept that the inflammatory SNC secretory phenotype could be pharmacologically inhibited using an approved drug (rapamycin).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Chang, J. et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat. Med. 22, 78–83 (2016). First demonstration that pharmacological inhibition of anti-apoptotic BCL-2 family members shows senescent cell killing (senolytic) activity.

    CAS  PubMed  Google Scholar 

  22. Wang, Y. et al. Discovery of piperlongumine as a potential novel lead for the development of senolytic agents. Aging 8, 2915–2926 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Zhu, Y. et al. The Achilles' heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14, 644–658 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Yosef, R. et al. Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nat. Commun. 7, 11190 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Karatza, C., Stein, W. D. & Shall, S. Kinetics of in vitro ageing of mouse embryo fibroblasts. J. Cell Sci. 65, 163–175 (1984).

    CAS  PubMed  Google Scholar 

  26. Ponten, J., Stein, W. D. & Shall, S. A quantitative analysis of the aging of human glial cells in culture. J. Cell. Physiol. 117, 342–352 (1983).

    CAS  PubMed  Google Scholar 

  27. Cristofalo, V. J. & Sharf, B. B. Cellular senescence and DNA synthesis. Thymidine incorporation as a measure of population age in human diploid cells. Exp. Cell Res. 76, 419–427 (1973).

    CAS  PubMed  Google Scholar 

  28. Hayflick, L. The limited in vitro lifetime of human diploid cell strains. Exp. Cell Res. 37, 614–636 (1965).

    CAS  PubMed  Google Scholar 

  29. Dimri, G. P. et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl Acad. Sci. USA 92, 9363–9367 (1995). This study reports the development of the SA- β -Gal stain, which is a widely used biomarker for detecting SNCs in vitro and in vivo.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Serrano, M., Hannon, G. J. & Beach, D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 366, 704–707 (1993).

    CAS  PubMed  Google Scholar 

  31. Alcorta, D. A. et al. Involvement of the cyclin-dependent kinase inhibitor p16INK4a in replicative senescence of normal human fibroblasts. Proc. Natl Acad. Sci. USA 93, 13742–13747 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Serrano, M. et al. Role of the INK4a locus in tumor suppression and cell mortality. Cell 85, 27–37 (1996).

    CAS  PubMed  Google Scholar 

  33. Beausejour, C. M. et al. Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO J. 22, 4212–4222 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Chen, Z. et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436, 725–730 (2005). This is a first example of a loss of tumour suppressor function (PTEN insufficiency), which results in cellular senescence.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Evangelou, K. et al. Robust, universal biomarker assay to detect senescent cells in biological specimens. Aging Cell 16, 192–197 (2017).

    CAS  PubMed  Google Scholar 

  36. Minamino, T. et al. Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction. Circulation 105, 1541–1544 (2002).

    CAS  PubMed  Google Scholar 

  37. Krishnamurthy, J. et al. Ink4a/Arf expression is a biomarker of aging. J. Clin. Invest. 114, 1299–1307 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D. & Lowe, S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593–602 (1997).

    CAS  PubMed  Google Scholar 

  39. Aguilera, A. & Garcia-Muse, T. Causes of genome instability. Annu. Rev. Genet. 47, 1–32 (2013).

    CAS  PubMed  Google Scholar 

  40. Davoli, T., Denchi, E. L. & de Lange, T. Persistent telomere damage induces bypass of mitosis and tetraploidy. Cell 141, 81–93 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Coppe, J. P. et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 6, 2853–2868 (2008).

    CAS  PubMed  Google Scholar 

  42. Coppe, J. P. et al. A human-like senescence-associated secretory phenotype is conserved in mouse cells dependent on physiological oxygen. PLoS ONE 5, e9188 (2010).

    PubMed  PubMed Central  Google Scholar 

  43. Rodier, F. et al. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat. Cell Biol. 11, 973–979 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Rodier, F. et al. DNA-SCARS: distinct nuclear structures that sustain damage-induced senescence growth arrest and inflammatory cytokine secretion. J. Cell Sci. 124, 68–81 (2011).

    CAS  PubMed  Google Scholar 

  45. Sturmlechner, I., Durik, M., Sieben, C. J., Baker, D. J. & van Deursen, J. M. Cellular senescence in renal ageing and disease. Nat. Rev. Nephrol. 13, 77–89 (2017).

    CAS  PubMed  Google Scholar 

  46. Childs, B. G., Durik, M., Baker, D. J. & van Deursen, J. M. Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat. Med. 21, 1424–1435 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Alimonti, A. et al. A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis. J. Clin. Invest. 120, 681–693 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Bartkova, J. et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444, 633–637 (2006).

    CAS  PubMed  Google Scholar 

  49. Pluquet, O., Pourtier, A. & Abbadie, C. The unfolded protein response and cellular senescence. A review in the theme: cellular mechanisms of endoplasmic reticulum stress signaling in health and disease. Am. J. Physiol. Cell Physiol. 308, C415–C425 (2015).

    CAS  PubMed  Google Scholar 

  50. Shiloh, Y. & Ziv, Y. The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nat. Rev. Mol. Cell Biol. 14, 197–210 (2013).

    CAS  PubMed  Google Scholar 

  51. Eischen, C. M. & Lozano, G. The Mdm network and its regulation of p53 activities: a rheostat of cancer risk. Hum. Mutat. 35, 728–737 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Herbig, U., Wei, W., Dutriaux, A., Jobling, W. A. & Sedivy, J. M. Real-time imaging of transcriptional activation in live cells reveals rapid up-regulation of the cyclin-dependent kinase inhibitor gene CDKN1A in replicative cellular senescence. Aging Cell 2, 295–304 (2003).

    CAS  PubMed  Google Scholar 

  53. Wong, E. S. et al. p38MAPK controls expression of multiple cell cycle inhibitors and islet proliferation with advancing age. Dev. Cell 17, 142–149 (2009).

    CAS  PubMed  Google Scholar 

  54. Ohtani, N. et al. Opposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence. Nature 409, 1067–1070 (2001).

    CAS  PubMed  Google Scholar 

  55. Takahashi, A. et al. Mitogenic signalling and the p16INK4a-Rb pathway cooperate to enforce irreversible cellular senescence. Nat. Cell Biol. 8, 1291–1297 (2006).

    CAS  PubMed  Google Scholar 

  56. Johmura, Y. et al. Necessary and sufficient role for a mitosis skip in senescence induction. Mol. Cell 55, 73–84 (2014).

    CAS  PubMed  Google Scholar 

  57. Le, O. N. et al. Ionizing radiation-induced long-term expression of senescence markers in mice is independent of p53 and immune status. Aging Cell 9, 398–409 (2010).

    CAS  PubMed  Google Scholar 

  58. Acosta, J. C. et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133, 1006–1018 (2008).

    CAS  PubMed  Google Scholar 

  59. Kuilman, T. et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133, 1019–1031 (2008). References 41, 58 and 59 established that the secretory profile of SNCs is a hallmark of this cell type.

    CAS  PubMed  Google Scholar 

  60. Acosta, J. C. et al. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat. Cell Biol. 15, 978–990 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Kuilman, T. & Peeper, D. S. Senescence-messaging secretome: SMS-ing cellular stress. Nat. Rev. Cancer 9, 81–94 (2009).

    CAS  PubMed  Google Scholar 

  62. Campisi, J. & d'Adda di Fagagna, F. Cellular senescence: when bad things happen to good cells. Nat. Rev. Mol. Cell Biol. 8, 729–740 (2007).

    CAS  PubMed  Google Scholar 

  63. Freund, A., Patil, C. K. & Campisi, J. p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype. EMBO J. 30, 1536–1548 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Hoare, M. et al. NOTCH1 mediates a switch between two distinct secretomes during senescence. Nat. Cell Biol. 18, 979–992 (2016). This study demonstrated that the SNC secretory profile changes composition over time to coordinate distinct paracrine signalling events to immune cells and surrounding tissue.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Orjalo, A. V., Bhaumik, D., Gengler, B. K., Scott, G. K. & Campisi, J. Cell surface-bound IL-1alpha is an upstream regulator of the senescence-associated IL-6/IL-8 cytokine network. Proc. Natl Acad. Sci. USA 106, 17031–17036 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Eyman, D., Damodarasamy, M., Plymate, S. R. & Reed, M. J. CCL5 secreted by senescent aged fibroblasts induces proliferation of prostate epithelial cells and expression of genes that modulate angiogenesis. J. Cell. Physiol. 220, 376–381 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Luo, X. et al. Stromal-initiated changes in the bone promote metastatic niche development. Cell Rep. 14, 82–92 (2016).

    CAS  PubMed  Google Scholar 

  68. Angelini, P. D. et al. Constitutive HER2 signaling promotes breast cancer metastasis through cellular senescence. Cancer Res. 73, 6095–6095 (2013).

    CAS  Google Scholar 

  69. Ruhland, M. K. et al. Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis. Nat. Commun. 7, 11762 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Eggert, T. et al. Distinct functions of senescence-associated immune responses in liver tumor surveillance and tumor progression. Cancer Cell 30, 533–547 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Ritschka, B. et al. The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration. Genes Dev. 31, 172–183 (2017). This work implicated signals arising from the SNC secretome to stemness during tissue regeneration.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Inoue, K. et al. Serial coronary CT angiography-verified changes in plaque characteristics as an end point: evaluation of effect of statin intervention. JACC Cardiovasc. Imaging 3, 691–698 (2010).

    PubMed  Google Scholar 

  73. Eren, M. et al. PAI-1-regulated extracellular proteolysis governs senescence and survival in Klotho mice. Proc. Natl Acad. Sci. USA 111, 7090–7095 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Liu, D. & Hornsby, P. J. Senescent human fibroblasts increase the early growth of xenograft tumors via matrix metalloproteinase secretion. Cancer Res. 67, 3117–3126 (2007).

    CAS  PubMed  Google Scholar 

  75. Childs, B. G., Baker, D. J., Kirkland, J. L., Campisi, J. & van Deursen, J. M. Senescence and apoptosis: dueling or complementary cell fates? EMBO Rep. 15, 1139–1153 (2014). This review gives a broad overview of the possible advantages of senescence compared with apoptosis as a fate for damaged cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Burton, D. G. & Faragher, R. G. Cellular senescence: from growth arrest to immunogenic conversion. Age (Dordr.) 37, 27 (2015).

    CAS  Google Scholar 

  77. Tavana, O. et al. Absence of p53-dependent apoptosis leads to UV radiation hypersensitivity, enhanced immunosuppression and cellular senescence. Cell Cycle 9, 3328–3336 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Webley, K. et al. Posttranslational modifications of p53 in replicative senescence overlapping but distinct from those induced by DNA damage. Mol. Cell. Biol. 20, 2803–2808 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Timofeev, O. et al. p53 DNA binding cooperativity is essential for apoptosis and tumor suppression in vivo. Cell Rep. 3, 1512–1525 (2013).

    CAS  PubMed  Google Scholar 

  80. Zhang, Y. et al. DNMT3a plays a role in switches between doxorubicin-induced senescence and apoptosis of colorectal cancer cells. Int. J. Cancer 128, 551–561 (2011).

    CAS  PubMed  Google Scholar 

  81. Hayward, R. L. et al. Antisense Bcl-xl down-regulation switches the response to topoisomerase I inhibition from senescence to apoptosis in colorectal cancer cells, enhancing global cytotoxicity. Clin. Cancer Res. 9, 2856–2865 (2003).

    CAS  PubMed  Google Scholar 

  82. Tang, J. J., Shen, C. & Lu, Y. J. Requirement for pre-existing of p21 to prevent doxorubicin-induced apoptosis through inhibition of caspase-3 activation. Mol. Cell. Biochem. 291, 139–144 (2006).

    CAS  PubMed  Google Scholar 

  83. Hanks, S. et al. Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B. Nat. Genet. 36, 1159–1161 (2004).

    CAS  PubMed  Google Scholar 

  84. Donehower, L. A. The p53-deficient mouse: a model for basic and applied cancer studies. Semin. Cancer Biol. 7, 269–278 (1996).

    CAS  PubMed  Google Scholar 

  85. Krimpenfort, P., Quon, K. C., Mooi, W. J., Loonstra, A. & Berns, A. Loss of p16Ink4a confers susceptibility to metastatic melanoma in mice. Nature 413, 83–86 (2001).

    CAS  PubMed  Google Scholar 

  86. Schafer, M. J. et al. Cellular senescence mediates fibrotic pulmonary disease. Nat. Commun. 8, 14532 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Kang, T. W. et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479, 547–551 (2011). This work demonstrates that the anticancer effects of cellular senescence extend beyond cell cycle arrest, in particular that SNCs may promote recruitment of tumour-suppressive immune effectors.

    CAS  PubMed  Google Scholar 

  88. Krtolica, A., Parrinello, S., Lockett, S., Desprez, P. Y. & Campisi, J. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc. Natl Acad. Sci. USA 98, 12072–12077 (2001). This study provided early support for the hypothesis that SNCs promote carcinogenesis in a cell non-autonomous fashion.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Bar-Shai, A., Sagiv, A., Alon, R. & Krizhanovsky, V. The role of Clara cell senescence in the pathogenesis of COPD. Eur. Respir. J. 44, 3245 (2014).

    Google Scholar 

  90. Bhat, R. et al. Astrocyte senescence as a component of Alzheimer's disease. PLoS ONE 7, e45069 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Demaria, M. et al. Cellular senescence promotes adverse effects of chemotherapy and cancer relapse. Cancer Discov. 7, 165–176 (2017).

    CAS  PubMed  Google Scholar 

  92. Freund, A., Laberge, R. M., Demaria, M. & Campisi, J. Lamin B1 loss is a senescence-associated biomarker. Mol. Biol. Cell 23, 2066–2075 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Laberge, R. M. et al. Mitochondrial DNA damage induces apoptosis in senescent cells. Cell Death Dis. 4, e727 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Demaria, M., Desprez, P. Y., Campisi, J. & Velarde, M. C. Cell autonomous and non-autonomous effects of senescent cells in the skin. J. Invest. Dermatol. 135, 1722–1726 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Roberts, S., Evans, E. H., Kletsas, D., Jaffray, D. C. & Eisenstein, S. M. Senescence in human intervertebral discs. Eur. Spine J. 15 (Suppl. 3), S312–S316 (2006).

    Google Scholar 

  96. Le Maitre, C. L., Freemont, A. J. & Hoyland, J. A. Accelerated cellular senescence in degenerate intervertebral discs: a possible role in the pathogenesis of intervertebral disc degeneration. Arthritis Res. Ther. 9, R45 (2007).

    PubMed  PubMed Central  Google Scholar 

  97. Sousa-Victor, P. et al. Geriatric muscle stem cells switch reversible quiescence into senescence. Nature 506, 316–321 (2014).

    CAS  PubMed  Google Scholar 

  98. Cosgrove, B. D. et al. Rejuvenation of the muscle stem cell population restores strength to injured aged muscles. Nat. Med. 20, 255–264 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Bernet, J. D. et al. p38 MAPK signaling underlies a cell-autonomous loss of stem cell self-renewal in skeletal muscle of aged mice. Nat. Med. 20, 265–271 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Du, J. et al. Aging increases CCN1 expression leading to muscle senescence. Am. J. Physiol. Cell Physiol. 306, C28–C36 (2014).

    CAS  PubMed  Google Scholar 

  101. Finn, A. V., Nakano, M., Narula, J., Kolodgie, F. D. & Virmani, R. Concept of vulnerable/unstable plaque. Arterioscler. Thromb. Vasc. Biol. 30, 1282–1292 (2010).

    CAS  PubMed  Google Scholar 

  102. Tabas, I., Garcia-Cardena, G. & Owens, G. K. Recent insights into the cellular biology of atherosclerosis. J. Cell Biol. 209, 13–22 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Weber, C. & Noels, H. Atherosclerosis: current pathogenesis and therapeutic options. Nat. Med. 17, 1410–1422 (2011).

    CAS  PubMed  Google Scholar 

  104. Berenbaum, F. Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis!). Osteoarthritis Cartilage 21, 16–21 (2013).

    CAS  PubMed  Google Scholar 

  105. Wieland, H. A., Michaelis, M., Kirschbaum, B. J. & Rudolphi, K. A. Osteoarthritis — an untreatable disease? Nat. Rev. Drug Discov. 4, 331–344 (2005).

    CAS  PubMed  Google Scholar 

  106. Lawrence, R. C. et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum. 58, 26–35 (2008).

    PubMed  PubMed Central  Google Scholar 

  107. March, L., Amatya, B., Osborne, R. H. & Brand, C. Developing a minimum standard of care for treating people with osteoarthritis of the hip and knee. Best Pract. Res. Clin. Rheumatol. 24, 121–145 (2010).

    PubMed  Google Scholar 

  108. Krizhanovsky, V. et al. Senescence of activated stellate cells limits liver fibrosis. Cell 134, 657–667 (2008). This work shows a beneficial function (fibrosis restriction) for cellular senescence beyond tumour suppression.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Luna-Vargas, M. P. & Chipuk, J. E. Physiological and pharmacological control of BAK, BAX, and beyond. Trends Cell Biol. 26, 906–917 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Tse, C. et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 68, 3421–3428 (2008).

    CAS  PubMed  Google Scholar 

  111. Zhu, Y. et al. Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell 15, 428–435 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Bai, L. & Wang, S. Targeting apoptosis pathways for new cancer therapeutics. Annu. Rev. Med. 65, 139–155 (2014).

    CAS  PubMed  Google Scholar 

  113. Weisberg, E., Manley, P. W., Cowan-Jacob, S. W., Hochhaus, A. & Griffin, J. D. Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukaemia. Nat. Rev. Cancer 7, 345–356 (2007).

    CAS  PubMed  Google Scholar 

  114. Boots, A. W., Haenen, G. R. & Bast, A. Health effects of quercetin: from antioxidant to nutraceutical. Eur. J. Pharmacol. 585, 325–337 (2008).

    CAS  PubMed  Google Scholar 

  115. Chondrogianni, N. et al. Anti-ageing and rejuvenating effects of quercetin. Exp. Gerontol. 45, 763–771 (2010).

    CAS  PubMed  Google Scholar 

  116. Baar, M. P. et al. Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell 169, 132–147.e16 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Roos, C. M. et al. Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell 15, 973–977 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Kloss, C. C., Condomines, M., Cartellieri, M., Bachmann, M. & Sadelain, M. Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells. Nat. Biotechnol. 31, 71–75 (2013).

    CAS  PubMed  Google Scholar 

  119. Xue, W. et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445, 656–660 (2007). This work tested and validated the hypothesis that SNCs can be removed by the immune system and provided support for the idea that the SNC secretome drives this immune surveillance.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Vindrieux, D. et al. Down-regulation of DcR2 sensitizes androgen-dependent prostate cancer LNCaP cells to TRAIL-induced apoptosis. Cancer Cell Int. 11, 42 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Zhang, Z., Rosen, D. G., Yao, J. L., Huang, J. & Liu, J. Expression of p14ARF, p15INK4b, p16INK4a, and DCR2 increases during prostate cancer progression. Mod. Pathol. 19, 1339–1343 (2006).

    CAS  PubMed  Google Scholar 

  122. Aydin, C. et al. Decoy receptor-2 small interfering RNA (siRNA) strategy employing three different siRNA constructs in combination defeats adenovirus-transferred tumor necrosis factor-related apoptosis-inducing ligand resistance in lung cancer cells. Hum. Gene Ther. 18, 39–50 (2007).

    CAS  PubMed  Google Scholar 

  123. Wu, Q. et al. Aberrant expression of decoy receptor 3 in human breast cancer: relevance to lymphangiogenesis. J. Surg. Res. 188, 459–465 (2014).

    CAS  PubMed  Google Scholar 

  124. Ge, Z., Sanders, A. J., Ye, L. & Jiang, W. G. Aberrant expression and function of death receptor-3 and death decoy receptor-3 in human cancer. Exp. Ther. Med. 2, 167–172 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Sagiv, A. et al. Granule exocytosis mediates immune surveillance of senescent cells. Oncogene 32, 1971–1977 (2013).

    CAS  PubMed  Google Scholar 

  126. Boivin, W. A., Cooper, D. M., Hiebert, P. R. & Granville, D. J. Intracellular versus extracellular granzyme B in immunity and disease: challenging the dogma. Lab. Invest. 89, 1195–1220 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Collado, M. & Serrano, M. Senescence in tumours: evidence from mice and humans. Nat. Rev. Cancer 10, 51–57 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. He, J., Hu, Y., Hu, M. & Li, B. Development of PD-1/PD-L1 pathway in tumor immune microenvironment and treatment for non-small cell lung cancer. Sci. Rep. 5, 13110 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Konkel, J. E. et al. PD-1 signalling in CD4+ T cells restrains their clonal expansion to an immunogenic stimulus, but is not critically required for peptide-induced tolerance. Immunology 130, 92–102 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Yang, G. et al. The chemokine growth-regulated oncogene 1 (Gro-1) links RAS signaling to the senescence of stromal fibroblasts and ovarian tumorigenesis. Proc. Natl Acad. Sci. USA 103, 16472–16477 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Elzi, D. J. et al. Plasminogen activator inhibitor 1—insulin-like growth factor binding protein 3 cascade regulates stress-induced senescence. Proc. Natl Acad. Sci. USA 109, 12052–12057 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Chien, Y. et al. Control of the senescence-associated secretory phenotype by NF-kappaB promotes senescence and enhances chemosensitivity. Genes Dev. 25, 2125–2136 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Baroja-Mazo, A., Revilla-Nuin, B., Ramirez, P. & Pons, J. A. Immunosuppressive potency of mechanistic target of rapamycin inhibitors in solid-organ transplantation. World J. Transplant. 6, 183–192 (2016).

    PubMed  PubMed Central  Google Scholar 

  134. Capell, B. C. et al. MLL1 is essential for the senescence-associated secretory phenotype. Genes Dev. 30, 321–336 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Tasdemir, N. et al. BRD4 connects enhancer remodeling to senescence immune surveillance. Cancer Discov. 6, 612–629 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Aird, K. M. et al. HMGB2 orchestrates the chromatin landscape of senescence-associated secretory phenotype gene loci. J. Cell Biol. 215, 325–334 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Kojima, H., Inoue, T., Kunimoto, H. & Nakajima, K. IL-6-STAT3 signaling and premature senescence. JAK-STAT 2, e25763 (2013).

    PubMed  PubMed Central  Google Scholar 

  138. Lee, S. et al. A small molecule binding HMGB1 and HMGB2 inhibits microglia-mediated neuroinflammation. Nat. Chem. Biol. 10, 1055–1060 (2014).

    CAS  PubMed  Google Scholar 

  139. Lehmann, B. D. et al. Senescence-associated exosome release from human prostate cancer cells. Cancer Res. 68, 7864–7871 (2008).

    CAS  PubMed  Google Scholar 

  140. Xin, M. G., Zhang, J., Block, E. R. & Patel, J. M. Senescence-enhanced oxidative stress is associated with deficiency of mitochondrial cytochrome c oxidase in vascular endothelial cells. Mech. Ageing Dev. 124, 911–919 (2003).

    CAS  PubMed  Google Scholar 

  141. Effenberger, T. et al. Senescence-associated release of transmembrane proteins involves proteolytic processing by ADAM17 and microvesicle shedding. FASEB J. 28, 4847–4856 (2014).

    CAS  PubMed  Google Scholar 

  142. Iannello, A., Thompson, T. W., Ardolino, M., Lowe, S. W. & Raulet, D. H. p53-dependent chemokine production by senescent tumor cells supports NKG2D-dependent tumor elimination by natural killer cells. J. Exp. Med. 210, 2057–2069 (2013).

    CAS  PubMed  Google Scholar 

  143. Rovillain, E. et al. Activation of nuclear factor-kappa B signalling promotes cellular senescence. Oncogene 30, 2356–2366 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Afonina, I. S., Muller, C., Martin, S. J. & Beyaert, R. Proteolytic processing of interleukin-1 family cytokines: variations on a common theme. Immunity 42, 991–1004 (2015).

    CAS  PubMed  Google Scholar 

  145. McCarthy, D. A., Clark, R. R., Bartling, T. R., Trebak, M. & Melendez, J. A. Redox control of the senescence regulator interleukin-1alpha and the secretory phenotype. J. Biol. Chem. 288, 32149–32159 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. McQuibban, G. A. et al. Matrix metalloproteinase processing of monocyte chemoattractant proteins generates CC chemokine receptor antagonists with anti-inflammatory properties in vivo. Blood 100, 1160–1167 (2002).

    CAS  PubMed  Google Scholar 

  147. van Rhee, F. et al. Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial. Lancet Oncol. 15, 966–974 (2014).

    CAS  PubMed  Google Scholar 

  148. Emery, P. et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann. Rheum. Dis. 67, 1516–1523 (2008).

    CAS  PubMed  Google Scholar 

  149. Mobasheri, A., Bay-Jensen, A. C., van Spil, W. E., Larkin, J. & Levesque, M. C. Osteoarthritis year in review 2016: biomarkers (biochemical markers). Osteoarthritis Cartilage 25, 199–208 (2017).

    CAS  PubMed  Google Scholar 

  150. Fernandez-Puente, P. et al. Identification of a panel of novel serum osteoarthritis biomarkers. J. Proteome Res. 10, 5095–5101 (2011).

    CAS  PubMed  Google Scholar 

  151. Kraus, V. B. et al. OARSI clinical trials recommendations: soluble biomarker assessments in clinical trials in osteoarthritis. Osteoarthritis Cartilage 23, 686–697 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Bay-Jensen, A. C. et al. Osteoarthritis year in review 2015: soluble biomarkers and the BIPED criteria. Osteoarthritis Cartilage 24, 9–20 (2016).

    CAS  PubMed  Google Scholar 

  153. Ahmed, U. et al. Biomarkers of early stage osteoarthritis, rheumatoid arthritis and musculoskeletal health. Sci. Rep. 5, 9259 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Schwarzenbach, H., Hoon, D. S. B. & Pantel, K. Cell-free nucleic acids as biomarkers in cancer patients. Nat. Rev. Cancer 11, 426–437 (2011).

    CAS  PubMed  Google Scholar 

  155. Agostini, A. et al. Targeted cargo delivery in senescent cells using capped mesoporous silica nanoparticles. Angew. Chem. Int. Ed. 51, 10556–10560 (2012).

    CAS  Google Scholar 

  156. Polakis, P. Antibody drug conjugates for cancer therapy. Pharmacol. Rev. 68, 3–19 (2016).

    CAS  PubMed  Google Scholar 

  157. Frescas, D. et al. Senescent cells expose and secrete an oxidized form of membrane-bound vimentin as revealed by a natural polyreactive antibody. Proc. Natl Acad. Sci. USA 114, E1668–E1677 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Collado, M. et al. Tumour biology: senescence in premalignant tumours. Nature 436, 642 (2005).

    CAS  PubMed  Google Scholar 

  159. Althubiti, M. et al. Characterization of novel markers of senescence and their prognostic potential in cancer. Cell Death Dis. 5, e1528 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Kaefer, A. et al. Mechanism-based pharmacokinetic/pharmacodynamic meta-analysis of navitoclax (ABT-263) induced thrombocytopenia. Cancer Chemother. Pharmacol. 74, 593–602 (2014).

    CAS  PubMed  Google Scholar 

  161. Sharpless, N. E. et al. Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis. Nature 413, 86–91 (2001). This is an important demonstration of the tumour-suppressive properties of a key senescence effector, p16INK4A.

    CAS  PubMed  Google Scholar 

  162. Barzilai, N., Crandall, J. P., Kritchevsky, S. B. & Espeland, M. A. Metformin as a tool to target aging. Cell Metab. 23, 1060–1065 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Jun, J. I. & Lau, L. F. The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing. Nat. Cell Biol. 12, 676–685 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Sharpless, N. E., Ramsey, M. R., Balasubramanian, P., Castrillon, D. H. & DePinho, R. A. The differential impact of p16INK4a or p19ARF deficiency on cell growth and tumorigenesis. Oncogene 23, 379–385 (2004).

    CAS  PubMed  Google Scholar 

  165. Cairns, P. et al. Frequency of homozygous deletion at p16/CDKN2 in primary human tumours. Nat. Genet. 11, 210–212 (1995).

    CAS  PubMed  Google Scholar 

  166. Herman, J. G. et al. Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers. Cancer Res. 55, 4525–4530 (1995).

    CAS  PubMed  Google Scholar 

  167. 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. 1, 686–692 (1995).

    CAS  PubMed  Google Scholar 

  168. Khanna, A. K. Enhanced susceptibility of cyclin kinase inhibitor p21 knockout mice to high fat diet induced atherosclerosis. J. Biomed. Sci. 16, 66 (2009).

    PubMed  PubMed Central  Google Scholar 

  169. Visel, A. et al. Targeted deletion of the 9p21 non-coding coronary artery disease risk interval in mice. Nature 464, 409–412 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Chiche, A. et al. Injury-induced senescence enables in vivo reprogramming in skeletal muscle. Cell Stem Cell 20, 407–414.e4 (2017).

    CAS  PubMed  Google Scholar 

  171. Guan, X. et al. Stromal senescence by prolonged CDK4/6 inhibition potentiates tumor growth. Mol. Cancer Res. 15, 237–249 (2017).

    CAS  PubMed  Google Scholar 

  172. Cheung-Ong, K., Giaever, G. & Nislow, C. DNA-damaging agents in cancer chemotherapy: serendipity and chemical biology. Chem. Biol. 20, 648–659 (2013).

    CAS  PubMed  Google Scholar 

  173. Yeh, C. K. Cellular senescence and aging. Oral Dis. 22, 587–590 (2016).

    PubMed  Google Scholar 

  174. Oeffinger, K. C. et al. Chronic health conditions in adult survivors of childhood cancer. N. Engl. J. Med. 355, 1572–1582 (2006).

    CAS  PubMed  Google Scholar 

  175. Schuitema, I. et al. Accelerated aging, decreased white matter integrity, and associated neuropsychological dysfunction 25 years after pediatric lymphoid malignancies. J. Clin. Oncol. 31, 3378–3388 (2013).

    PubMed  Google Scholar 

  176. Dorth, J. A., Patel, P. R., Broadwater, G. & Brizel, D. M. Incidence and risk factors of significant carotid artery stenosis in asymptomatic survivors of head and neck cancer after radiotherapy. Head Neck 36, 215–219 (2014).

    PubMed  Google Scholar 

  177. Anzidei, M. et al. Longitudinal assessment of carotid atherosclerosis after radiation therapy using computed tomography: a case control Study. Eur. Radiol. 26, 72–78 (2016).

    PubMed  Google Scholar 

  178. Wildiers, H. et al. International Society of Geriatric Oncology consensus on geriatric assessment in older patients with cancer. J. Clin. Oncol. 32, 2595–2603 (2014).

    PubMed  PubMed Central  Google Scholar 

  179. Yip, C. et al. Assessment of sarcopenia and changes in body composition after neoadjuvant chemotherapy and associations with clinical outcomes in oesophageal cancer. Eur. Radiol. 24, 998–1005 (2014).

    PubMed  Google Scholar 

  180. Armstrong, G. T. et al. Aging and risk of severe, disabling, life-threatening, and fatal events in the childhood cancer survivor study. J. Clin. Oncol. 32, 1218–1227 (2014).

    PubMed  PubMed Central  Google Scholar 

  181. Coppe, J. P. et al. Tumor suppressor and aging biomarker p16INK4a induces cellular senescence without the associated inflammatory secretory phenotype. J. Biol. Chem. 286, 36396–36403 (2011). This work clearly demonstrated the separability of the SNC secretome from cell cycle arrest.

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Lan, L. et al. Shp2 signaling suppresses senescence in PyMT-induced mammary gland cancer in mice. EMBO J. 34, 2383 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Serrano, M. SHP2: a new target for pro-senescence cancer therapies. EMBO J. 34, 1439–1441 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Fukazawa, R. et al. Coronary artery aneurysm induced by Kawasaki disease in children show features typical senescence. Circ. J. 71, 709–715 (2007).

    PubMed  Google Scholar 

  185. Liton, P. B. et al. Cellular senescence in the glaucomatous outflow pathway. Exp. Gerontol. 40, 745–748 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Zhu, D., Wu, J., Spee, C., Ryan, S. J. & Hinton, D. R. BMP4 mediates oxidative stress-induced retinal pigment epithelial cell senescence and is overexpressed in age-related macular degeneration. J. Biol. Chem. 284, 9529–9539 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Mishima, K. et al. Senescence-associated beta-galactosidase histochemistry for the primate eye. Invest. Ophthalmol. Vis. Sci. 40, 1590–1593 (1999).

    CAS  PubMed  Google Scholar 

  188. Sohn, J. J. et al. Macrophages, nitric oxide and microRNAs are associated with DNA damage response pathway and senescence in inflammatory bowel disease. PLoS ONE 7, e44156 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Martin, J. A., Brown, T. D., Heiner, A. D. & Buckwalter, J. A. Chondrocyte senescence, joint loading and osteoarthritis. Clin. Orthop. Relat. Res. 427 (Suppl.), S96–S103 (2004).

    Google Scholar 

  190. Yanai, H. et al. Cellular senescence-like features of lung fibroblasts derived from idiopathic pulmonary fibrosis patients. Aging 7, 664–672 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Aoshiba, K., Tsuji, T. & Nagai, A. Bleomycin induces cellular senescence in alveolar epithelial cells. Eur. Respir. J. 22, 436–443 (2003).

    CAS  PubMed  Google Scholar 

  192. Aoshiba, K. et al. Senescence-associated secretory phenotype in a mouse model of bleomycin-induced lung injury. Exp. Toxicol. Pathol. 65, 1053–1062 (2013).

    CAS  PubMed  Google Scholar 

  193. Fischer, B. M. et al. Increased expression of senescence markers in cystic fibrosis airways. Am. J. Physiol. Lung Cell. Mol. Physiol. 304, L394–L400 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  194. Markowski, D. N. et al. HMGA2 expression in white adipose tissue linking cellular senescence with diabetes. Genes Nutr. 8, 449–456 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Minamino, T. et al. A crucial role for adipose tissue p53 in the regulation of insulin resistance. Nat. Med. 15, 1082–1087 (2009).

    CAS  PubMed  Google Scholar 

  196. Fitzner, B. et al. Senescence determines the fate of activated rat pancreatic stellate cells. J. Cell. Mol. Med. 16, 2620–2630 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Morgan, R. G. et al. Role of arterial telomere dysfunction in hypertension: relative contributions of telomere shortening and telomere uncapping. J. Hypertension 32, 1293–1299 (2014).

    CAS  Google Scholar 

  198. Mercer, J., Figg, N., Stoneman, V., Braganza, D. & Bennett, M. R. Endogenous p53 protects vascular smooth muscle cells from apoptosis and reduces atherosclerosis in ApoE knockout mice. Circ. Res. 96, 667–674 (2005).

    CAS  PubMed  Google Scholar 

  199. Diez-Juan, A. & Andres, V. The growth suppressor p27(Kip1) protects against diet-induced atherosclerosis. FASEB J. 15, 1989–1995 (2001).

    CAS  PubMed  Google Scholar 

  200. Baker, D. J., Weaver, R. L. & van Deursen, J. M. p21 both attenuates and drives senescence and aging in BubR1 progeroid mice. Cell Rep. 3, 1164–1174 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. Braun, H. et al. Cellular senescence limits regenerative capacity and allograft survival. J. Am. Soc. Nephrol. 23, 1467–1473 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  202. Zhu, F. et al. Senescent cardiac fibroblast is critical for cardiac fibrosis after myocardial infarction. PLoS ONE 8, e74535 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Shivshankar, P. et al. Caveolin-1 deficiency protects from pulmonary fibrosis by modulating epithelial cell senescence in mice. Am. J. Respir. Cell Mol. Biol. 47, 28–36 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. Li, H. et al. FOXP1 controls mesenchymal stem cell commitment and senescence during skeletal aging. J. Clin. Invest. 127, 1241–1253 (2017).

    PubMed  PubMed Central  Google Scholar 

  205. Green, D. R. A. BH3 mimetic for killing cancer cells. Cell 165, 1560 (2016).

    CAS  PubMed  Google Scholar 

  206. Maruthur, N. M. et al. Diabetes medications as monotherapy or metformin-based combination therapy for type 2 diabetes: a systematic review and meta-analysis. Ann. Intern. Med. 164, 740–751 (2016).

    PubMed  Google Scholar 

  207. Moiseeva, O. et al. Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-kappaB activation. Aging Cell 12, 489–498 (2013).

    CAS  PubMed  Google Scholar 

  208. Noren Hooten, N. et al. Metformin-mediated increase in DICER1 regulates microRNA expression and cellular senescence. Aging Cell 15, 572–581 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  209. Webster, A. C., Lee, V. W., Chapman, J. R. & Craig, J. C. Target of rapamycin inhibitors (sirolimus and everolimus) for primary immunosuppression of kidney transplant recipients: a systematic review and meta-analysis of randomized trials. Transplantation 81, 1234–1248 (2006).

    CAS  PubMed  Google Scholar 

  210. Jobanputra, P., Barton, P., Bryan, S. & Burls, A. The effectiveness of infliximab and etanercept for the treatment of rheumatoid arthritis: a systematic review and economic evaluation. Health Technol. Assess. 6, 1–110 (2002).

    CAS  PubMed  Google Scholar 

  211. Kuemmerle-Deschner, J. B. et al. Canakinumab (ACZ885, a fully human IgG1 anti-IL-1beta mAb) induces sustained remission in pediatric patients with cryopyrin-associated periodic syndrome (CAPS). Arthritis Res. Ther. 13, R34 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. Hoffman, H. M. et al. Efficacy and safety of rilonacept (interleukin-1 Trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential placebo-controlled studies. Arthritis Rheum. 58, 2443–2452 (2008).

    CAS  PubMed  Google Scholar 

  213. Klareskog, L. et al. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet 363, 675–681 (2004).

    CAS  PubMed  Google Scholar 

  214. Cohen, S. et al. Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate: results of a twenty-four-week, multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 46, 614–624 (2002).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank N.David and Y.Poon of Unity Biotechnology for invaluable intellectual contributions to this Review and for thoroughly editing the text, and C.Yohn for feedback on the manuscript. The writing of this Review was supported by a grant from the Paul F.Glenn Foundation (J.M.v.D. and D.J.B.) and US National Institutes of Health (NIH) grants R01CA96985 and CA168709 (J.M.v.D.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jan M. van Deursen.

Ethics declarations

Competing interests

J.M.v.D. is a cofounder of Unity Biotechnology, which is a company developing senolytic medicines, including small molecules that selectively eliminate senescent cells. R.M.L., J.M.v.D., D.J.B. and B.G.C. are co-inventors on patent applications licensed to or filed by Unity Biotechnology. R.M.L., J.D. and D.M. are employed by Unity Biotechnology.

PowerPoint slides

Glossary

Senolysis

The therapeutic killing of senescent cells using small molecules (also known as senolytics).

Senescence

A tumour-suppressive cell fate undertaken in response to irreparable damage. It is characterized by permanent withdrawl from the cell cycle and acquisition of a pro-inflammatory, proteolytic secretome.

Senotherapies

Therapeutic strategies that aim to neutralize the deleterious effects of senescent cells as a treatment for age-related diseases.

Senescence-associated β-galactosidase

(SA-β-Gal). A lysosomal hydrolase with optimal activity at pH 6.0 in senescent cells (SNCs). Detection of SA-β-Gal enzymatic activity is frequently used to stain SNCs in vitro and in vivo.

Cyclin-dependent kinase inhibitor

(CDKi). A protein that arrests the cell cycle by binding to and deactivating cyclin-dependent kinases. p16INK4A, p19ARF, and p21 belong to this class of proteins and are commonly used as senescence markers.

Senescence-associated secretory phenotype

(SASP). The suite of secreted factors produced by senescent cells, including metalloproteinases, cytokines, chemokines, and growth factors, as well as non-protein metabolites.

Cytokines

Secreted protein factors that act as ligands for receptor- mediated cell signalling.

Chemokines

Cytokines, such as monocyte chemotactic protein 1 (MCP1), promote cellular migration (also known as chemotaxis).

BCL-2 family members

A protein class that consists of 25 members that share B cell lymphoma 2 (BCL-2) homology domains. These proteins either inhibit or promote mitochondrion-mediated apoptosis. BCL-2, BCL-W, and BCL-XL are three anti-apoptotic members that are inhibited by the senolytic and chemotherapeutic compound navitoclax.

High-mobility group box 1

(HMGB1). A member of a class of non-histone, chromatin proteins that modify transcription by binding to and distorting DNA. HMGB1 is released from senescent cells as an inflammatory 'alarmin'. Another member, HMGB2, is a positive regulator of senescence-associated secretory phenotype (SASP) factor transcription.

Metalloproteinases

A group of enzymes that cleave a peptide bond through the catalytic action of a coordinated metal ion (often zinc).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Childs, B., Gluscevic, M., Baker, D. et al. Senescent cells: an emerging target for diseases of ageing. Nat Rev Drug Discov 16, 718–735 (2017). https://doi.org/10.1038/nrd.2017.116

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd.2017.116

This article is cited by

Search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research