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.

  • Review Article
  • Published:

Senescence as a therapeutic target in cancer and age-related diseases

Nature Reviews Drug Discovery volume 24, pages 57–71 (2025)Cite this article

Subjects

Abstract

Cellular senescence is a stress response that restrains the growth of aged, damaged or abnormal cells. Thus, senescence has a crucial role in development, tissue maintenance and cancer prevention. However, lingering senescent cells fuel chronic inflammation through the acquisition of a senescence-associated secretory phenotype (SASP), which contributes to cancer and age-related tissue dysfunction. Recent progress in understanding senescence has spurred interest in the development of approaches to target senescent cells, known as senotherapies. In this Review, we evaluate the status of various types of senotherapies, including senolytics that eliminate senescent cells, senomorphics that suppress the SASP, interventions that mitigate senescence and strategies that harness the immune system to clear senescent cells. We also summarize how these approaches can be combined with cancer therapies, and we discuss the challenges and opportunities in moving senotherapies into clinical practice. Such therapies have the potential to address root causes of age-related diseases and thus open new avenues for preventive therapies and treating multimorbidities.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Fig. 1: Inducers and phenotypes associated with cellular senescence.
Fig. 2: Accumulation and turnover of senescent cells determine their effects and can be targeted with senotherapies.
Fig. 3: Different strategies to selectively eliminate senescent cells.
Fig. 4: Open questions and challenges to translate senotherapies to the clinic.

Similar content being viewed by others

References

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

    PubMed  Google Scholar 

  2. Hayflick, L. & Moorhead, P. S. The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585–621 (1961). This article is a pioneering study that defines the concept of cellular senescence.

    PubMed  Google Scholar 

  3. d’Adda di Fagagna, F. et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 426, 194–198 (2003).

    PubMed  Google Scholar 

  4. 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).

    PubMed  Google Scholar 

  5. Chang, B. D. et al. Role of p53 and p21waf1/cip1 in senescence-like terminal proliferation arrest induced in human tumor cells by chemotherapeutic drugs. Oncogene 18, 4808–4818 (1999).

    PubMed  Google Scholar 

  6. Schmitt, C. A. et al. A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell 109, 335–346 (2002). Together with Chang et al. (1999), this work describes the concept of TIS in human cells and mouse models for the first time.

    PubMed  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  8. Lee, S. et al. Virus-induced senescence is a driver and therapeutic target in COVID-19. Nature 599, 283–289 (2021).

    PubMed  Google Scholar 

  9. Di Micco, R., Krizhanovsky, V., Baker, D. & d’Adda di Fagagna, F. Cellular senescence in ageing: from mechanisms to therapeutic opportunities. Nat. Rev. Mol. Cell Biol. 22, 75–95 (2021).

    PubMed  Google Scholar 

  10. Storer, M. et al. Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell 155, 1119–1130 (2013).

    PubMed  Google Scholar 

  11. Munoz-Espin, D. et al. Programmed cell senescence during mammalian embryonic development. Cell 155, 1104–1118 (2013). Together with Storer et al. (2013), this work is the first study to describe developmental senescence.

    PubMed  Google Scholar 

  12. Krizhanovsky, V. et al. Senescence of activated stellate cells limits liver fibrosis. Cell 134, 657–667 (2008).

    PubMed  PubMed Central  Google Scholar 

  13. Michaloglou, C. et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436, 720–724 (2005).

    PubMed  Google Scholar 

  14. Braig, M. et al. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436, 660–665 (2005).

    PubMed  Google Scholar 

  15. Chen, Z. et al. Crucial role of p53-dependent cellular senescence in suppression of PTEN-deficient tumorigenesis. Nature 436, 725–730 (2005).

    PubMed  PubMed Central  Google Scholar 

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

    PubMed  Google Scholar 

  17. Baker, D. J. et al. Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature 530, 184–189 (2016). This article identifies the beneficial effects of senolysis in naturally aged mouse models.

    PubMed  PubMed Central  Google Scholar 

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

    PubMed  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  20. Sharpless, N. E. & Sherr, C. J. Forging a signature of in vivo senescence. Nat. Rev. Cancer 15, 397–408 (2015).

    PubMed  Google Scholar 

  21. Kaplon, J. et al. A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence. Nature 498, 109–112 (2013).

    PubMed  Google Scholar 

  22. Kondoh, H. et al. Glycolytic enzymes can modulate cellular life span. Cancer Res. 65, 177–185 (2005).

    PubMed  Google Scholar 

  23. Young, A. R. et al. Autophagy mediates the mitotic senescence transition. Genes. Dev. 23, 798–803 (2009).

    PubMed  PubMed Central  Google Scholar 

  24. Chandra, T. & Narita, M. High-order chromatin structure and the epigenome in SAHFs. Nucleus 4, 23–28 (2013).

    PubMed  PubMed Central  Google Scholar 

  25. Coppe, J. P., Desprez, P. Y., Krtolica, A. & Campisi, J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu. Rev. Pathol. 5, 99–118 (2010).

    PubMed  PubMed Central  Google Scholar 

  26. Kang, T. W. et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479, 547–551 (2011).

    PubMed  Google Scholar 

  27. Xue, W. et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445, 656–660 (2007). Together with Kang et al. (2011), this work is the first study to describe immune surveillance of SnCs.

    PubMed  PubMed Central  Google Scholar 

  28. Xu, M. et al. Senolytics improve physical function and increase lifespan in old age. Nat. Med. 24, 1246–1256 (2018).

    PubMed  PubMed Central  Google Scholar 

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

    PubMed  Google Scholar 

  30. 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).

    PubMed  PubMed Central  Google Scholar 

  31. 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).

    PubMed  PubMed Central  Google Scholar 

  32. Ritschka, B. et al. The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration. Genes. Dev. 31, 172–183 (2017).

    PubMed  PubMed Central  Google Scholar 

  33. Mosteiro, L. et al. Tissue damage and senescence provide critical signals for cellular reprogramming in vivo. Science 354, eaaf4445 (2016).

    Google Scholar 

  34. Yu, Q. et al. Cellular senescence promotes progenitor cell expansion during axolotl limb regeneration. Dev. Cell 58, 2416–2427.e7 (2023).

    PubMed  Google Scholar 

  35. Reyes, N. S. et al. Sentinel p16INK4a+ cells in the basement membrane form a reparative niche in the lung. Science 378, 192–201 (2022).

    PubMed  PubMed Central  Google Scholar 

  36. Grosse, L. et al. Defined p16High senescent cell types are indispensable for mouse healthspan. Cell Metab. 378, 87–99.e6 (2020). Together with Reyes et al. (2022), this work is the first study to describe a detrimental effect associated with eliminating specific populations of SnCs.

    Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  38. Wang, L., Lankhorst, L. & Bernards, R. Exploiting senescence for the treatment of cancer. Nat. Rev. Cancer 22, 340–355 (2022). This important Review summarizes the use of senotherapies for cancer.

    PubMed  Google Scholar 

  39. Di Micco, R. et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444, 638–642 (2006).

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  41. Faget, D. V., Ren, Q. & Stewart, S. A. Unmasking senescence: context-dependent effects of SASP in cancer. Nat. Rev. Cancer 19, 439–453 (2019).

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  43. Gonzalez-Meljem, J. M. et al. Stem cell senescence drives age-attenuated induction of pituitary tumours in mouse models of paediatric craniopharyngioma. Nat. Commun. 8, 1819 (2017).

    PubMed  PubMed Central  Google Scholar 

  44. Laberge, R. M., Awad, P., Campisi, J. & Desprez, P. Y. Epithelial–mesenchymal transition induced by senescent fibroblasts. Cancer Microenviron. 5, 39–44 (2011).

    PubMed  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  46. Di Mitri, D. et al. Tumour-infiltrating Gr-1+ myeloid cells antagonize senescence in cancer. Nature 515, 134–137 (2014). Together with Eggert et al. (2016), this work is the first study to describe the SASP-driven recruitment of immunosuppressive MDSCs.

    PubMed  Google Scholar 

  47. D’Ambrosio, M. & Gil, J. Reshaping of the tumor microenvironment by cellular senescence: an opportunity for senotherapies. Dev. Cell 58, 1007–1021 (2023).

    PubMed  Google Scholar 

  48. Yasuda, T. et al. Inflammation-driven senescence-associated secretory phenotype in cancer-associated fibroblasts enhances peritoneal dissemination. Cell Rep. 34, 108779 (2021).

    PubMed  Google Scholar 

  49. Prieto, L. I. et al. Senescent alveolar macrophages promote early-stage lung tumorigenesis. Cancer Cell 41, 1261–1275.e6 (2023).

    PubMed  PubMed Central  Google Scholar 

  50. Haston, S. et al. Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer. Cancer Cell 41, 1–19 (2023).

    Google Scholar 

  51. Maggiorani, D. et al. Senescence drives immunotherapy resistance by inducing an immunosuppressive tumor microenvironment. Nat. Commun. 15, 2435 (2024).

    PubMed  PubMed Central  Google Scholar 

  52. Wang, T. W. et al. Blocking PD-L1–PD-1 improves senescence surveillance and ageing phenotypes. Nature 611, 358–364 (2022).

    PubMed  Google Scholar 

  53. Chaib, S. et al. The efficacy of chemotherapy is limited by intratumoral senescent cells expressing PD-L2. Nat. Cancer 5, 448–462 (2024). Together with Wang et al. (2022), this work is the first study to describe the effect of immune checkpoint inhibitors on SnCs.

    PubMed  PubMed Central  Google Scholar 

  54. 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).

    PubMed  PubMed Central  Google Scholar 

  55. Kurz, D. J., Decary, S., Hong, Y. & Erusalimsky, J. D. Senescence-associated β-galactosidase reflects an increase in lysosomal mass during replicative ageing of human endothelial cells. J. Cell Sci. 113, 3613–3622 (2000).

    PubMed  Google Scholar 

  56. Gorgoulis, V. et al. Cellular senescence: defining a path forward. Cell 179, 813–827 (2019).

    PubMed  Google Scholar 

  57. Burd, C. E. et al. Monitoring tumorigenesis and senescence in vivo with a p16INK4a-luciferase model. Cell 152, 340–351 (2013).

    PubMed  PubMed Central  Google Scholar 

  58. Jeyapalan, J. C., Ferreira, M., Sedivy, J. M. & Herbig, U. Accumulation of senescent cells in mitotic tissue of aging primates. Mech. Ageing Dev. 128, 36–44 (2007).

    PubMed  Google Scholar 

  59. Tanaka, T. et al. Plasma proteomic signature of age in healthy humans. Aging Cell 17, e12799 (2018).

    PubMed  PubMed Central  Google Scholar 

  60. Omori, S. et al. Generation of a p16 reporter mouse and its use to characterize and target p16high cells in vivo. Cell Metab. 32, 814–828.e6 (2020).

    PubMed  Google Scholar 

  61. Karin, O., Agrawal, A., Porat, Z., Krizhanovsky, V. & Alon, U. Senescent cell turnover slows with age providing an explanation for the Gompertz law. Nat. Commun. 10, 5495 (2019).

    PubMed  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  63. Narasimhan, A., Flores, R. R., Robbins, P. D. & Niedernhofer, L. J. Role of cellular senescence in type II diabetes. Endocrinology 162, bqab136 (2021).

    PubMed  PubMed Central  Google Scholar 

  64. Gorenne, I., Kavurma, M., Scott, S. & Bennett, M. Vascular smooth muscle cell senescence in atherosclerosis. Cardiovasc. Res. 72, 9–17 (2006).

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  66. Papatheodoridi, A. M., Chrysavgis, L., Koutsilieris, M. & Chatzigeorgiou, A. The role of senescence in the development of nonalcoholic fatty liver disease and progression to nonalcoholic steatohepatitis. Hepatology 71, 363–374 (2020).

    PubMed  Google Scholar 

  67. Crespo-Garcia, S. et al. Pathological angiogenesis in retinopathy engages cellular senescence and is amenable to therapeutic elimination via BCL-xL inhibition. Cell Metab. 33, 818–832.e7 (2021).

    PubMed  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  69. Herdy, J. R. et al. Increased post-mitotic senescence in aged human neurons is a pathological feature of Alzheimer’s disease. Cell Stem Cell 29, 1637–1652.e6 (2022).

    PubMed  PubMed Central  Google Scholar 

  70. Zhang, L. et al. Cellular senescence: a key therapeutic target in aging and diseases. J. Clin. Invest. 132, e158450 (2022).

    PubMed  PubMed Central  Google Scholar 

  71. Baker, D. J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011).

    PubMed  PubMed Central  Google Scholar 

  72. Moiseeva, V. et al. Senescence atlas reveals an aged-like inflamed niche that blunts muscle regeneration. Nature 613, 169–178 (2023).

    PubMed  Google Scholar 

  73. Dungan, C. M. et al. Deletion of SA β-Gal+ cells using senolytics improves muscle regeneration in old mice. Aging Cell 21, e13528 (2022).

    PubMed  Google Scholar 

  74. Chang, J. et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat. Med. 22, 78–83 (2016).

    PubMed  Google Scholar 

  75. Wang, B. et al. An inducible p21-Cre mouse model to monitor and manipulate p21-highly-expressing senescent cells in vivo. Nat. Aging 1, 962–973 (2021).

    PubMed  PubMed Central  Google Scholar 

  76. Lee, S. et al. A guide to senolytic intervention in neurodegenerative disease. Mech. Ageing Dev. 200, 111585 (2021).

    PubMed  PubMed Central  Google Scholar 

  77. Zhang, P. et al. Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nat. Neurosci. 22, 719–728 (2019).

    PubMed  PubMed Central  Google Scholar 

  78. Ogrodnik, M. et al. Cellular senescence drives age-dependent hepatic steatosis. Nat. Commun. 8, 15691 (2017).

    PubMed  PubMed Central  Google Scholar 

  79. Childs, B. G. et al. Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science 354, 472–477 (2016).

    PubMed  PubMed Central  Google Scholar 

  80. Bigenwald, C. et al. BRAFV600E-induced senescence drives Langerhans cell histiocytosis pathophysiology. Nat. Med. 27, 851–861 (2021).

    PubMed  PubMed Central  Google Scholar 

  81. Wang, C. et al. Inducing and exploiting vulnerabilities for the treatment of liver cancer. Nature 574, 268–272 (2019).

    PubMed  PubMed Central  Google Scholar 

  82. Herranz, N. et al. mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype. Nat. Cell Biol. 17, 1205–1217 (2015).

    PubMed  PubMed Central  Google Scholar 

  83. 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).

    PubMed  PubMed Central  Google Scholar 

  84. Pospelova, T. V. et al. Suppression of replicative senescence by rapamycin in rodent embryonic cells. Cell Cycle 11, 2402–2407 (2012).

    PubMed  Google Scholar 

  85. Xu, Q. et al. The flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice. Nat. Metab. 3, 1706–1726 (2021).

    PubMed  PubMed Central  Google Scholar 

  86. Lopez-Otin, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).

    PubMed  PubMed Central  Google Scholar 

  87. Khosla, S. Senescent cells, senolytics and tissue repair: the devil may be in the dosing. Nat. Aging 3, 139–141 (2023).

    PubMed  PubMed Central  Google Scholar 

  88. Wang, E. Senescent human fibroblasts resist programmed cell death, and failure to suppress bcl2 is involved. Cancer Res. 55, 2284–2292 (1995).

    PubMed  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  90. 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). Together with Chang et al. (2016) and Yosef et al. (2016), this study is the first description of the use of BCL-2 inhibitors as senolytics.

    PubMed  PubMed Central  Google Scholar 

  91. Gandhi, L. et al. Phase I study of navitoclax (ABT-263), a novel Bcl-2 family inhibitor, in patients with small-cell lung cancer and other solid tumors. J. Clin. Oncol. 29, 909–916 (2011).

    PubMed  PubMed Central  Google Scholar 

  92. Munoz-Espin, D. et al. A versatile drug delivery system targeting senescent cells. EMBO Mol. Med. 10, e9355 (2018).

    PubMed  PubMed Central  Google Scholar 

  93. Gonzalez-Gualda, E. et al. Galacto-conjugation of navitoclax as an efficient strategy to increase senolytic specificity and reduce platelet toxicity. Aging Cell 19, e13142 (2020).

    PubMed  PubMed Central  Google Scholar 

  94. Jia, Y. et al. Co-targeting BCL-XL and BCL-2 by PROTAC 753B eliminates leukemia cells and enhances efficacy of chemotherapy by targeting senescent cells. Haematologica 108, 2626–2638 (2023).

    PubMed  PubMed Central  Google Scholar 

  95. He, Y. et al. Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity. Nat. Commun. 11, 1996 (2020).

    PubMed  PubMed Central  Google Scholar 

  96. Zhu, Y. et al. New agents that target senescent cells: the flavone, fisetin, and the BCL-X(L) inhibitors, A1331852 and A1155463. Aging 9, 955–963 (2017).

    PubMed  PubMed Central  Google Scholar 

  97. Thompson, P. J. et al. Targeted elimination of senescent β cells prevents type 1 diabetes. Cell Metab. 29, 1045–1060.e10 (2019).

    PubMed  Google Scholar 

  98. Troiani, M. et al. Single-cell transcriptomics identifies Mcl-1 as a target for senolytic therapy in cancer. Nat. Commun. 13, 2177 (2022).

    PubMed  PubMed Central  Google Scholar 

  99. Wang, L. et al. cFLIP suppression and DR5 activation sensitize senescent cancer cells to senolysis. Nat. Cancer 3, 1284–1299 (2022).

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  101. Guerrero, A. et al. Galactose-modified duocarmycin prodrugs as senolytics. Aging Cell 19, e13133 (2020).

    PubMed  PubMed Central  Google Scholar 

  102. Cai, Y. et al. Elimination of senescent cells by β-galactosidase-targeted prodrug attenuates inflammation and restores physical function in aged mice. Cell Res. 30, 574–589 (2020).

    PubMed  PubMed Central  Google Scholar 

  103. Efeyan, A. et al. Induction of p53-dependent senescence by the MDM2 antagonist nutlin-3a in mouse cells of fibroblast origin. Cancer Res. 67, 7350–7357 (2007).

    PubMed  Google Scholar 

  104. Dolgin, E. Send in the senolytics. Nat. Biotechnol. 38, 1371–1377 (2020).

    PubMed  Google Scholar 

  105. Li, M., Brooks, C. L., Kon, N. & Gu, W. A dynamic role of HAUSP in the p53–Mdm2 pathway. Mol. Cell 13, 879–886 (2004).

    PubMed  Google Scholar 

  106. He, Y. et al. Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity. Aging Cell 19, e13117 (2020).

    PubMed  PubMed Central  Google Scholar 

  107. 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).

    PubMed  PubMed Central  Google Scholar 

  108. Le, H. H. et al. Molecular modelling of the FOXO4–TP53 interaction to design senolytic peptides for the elimination of senescent cancer cells. EBioMedicine 73, 103646 (2021).

    PubMed  PubMed Central  Google Scholar 

  109. Wakita, M. et al. A BET family protein degrader provokes senolysis by targeting NHEJ and autophagy in senescent cells. Nat. Commun. 11, 1935 (2020).

    PubMed  PubMed Central  Google Scholar 

  110. Dorr, J. R. et al. Synthetic lethal metabolic targeting of cellular senescence in cancer therapy. Nature 501, 421–425 (2013). This article provides the first description of how targeting specific vulnerabilities can selectively eliminate SnCs.

    PubMed  Google Scholar 

  111. Correia-Melo, C. et al. Mitochondria are required for pro-ageing features of the senescent phenotype. EMBO J. 35, 724–742 (2016).

    PubMed  PubMed Central  Google Scholar 

  112. 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).

    PubMed  Google Scholar 

  113. Fuhrmann-Stroissnigg, H. et al. Identification of HSP90 inhibitors as a novel class of senolytics. Nat. Commun. 8, 422 (2017).

    PubMed  PubMed Central  Google Scholar 

  114. McHugh, D. et al. COPI vesicle formation and N-myristoylation are targetable vulnerabilities of senescent cells. Nat. Cell Biol. 25, 1804–1820 (2023).

    PubMed  PubMed Central  Google Scholar 

  115. Jackson, L. P. Structure and mechanism of COPI vesicle biogenesis. Curr. Opin. Cell Biol. 29, 67–73 (2014).

    PubMed  Google Scholar 

  116. Narita, M. et al. Spatial coupling of mTOR and autophagy augments secretory phenotypes. Science 332, 966–970 (2011).

    PubMed  PubMed Central  Google Scholar 

  117. Anerillas, C. et al. The YAP–TEAD complex promotes senescent cell survival by lowering endoplasmic reticulum stress. Nat. Aging 3, 1237–1250 (2023).

    PubMed  PubMed Central  Google Scholar 

  118. Johmura, Y. et al. Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders. Science 371, 265–270 (2021).

    PubMed  Google Scholar 

  119. Guerrero, A. et al. Cardiac glycosides are broad-spectrum senolytics. Nat. Metab. 1, 1074–1088 (2019).

    PubMed  PubMed Central  Google Scholar 

  120. Triana-Martinez, F. et al. Identification and characterization of cardiac glycosides as senolytic compounds. Nat. Commun. 10, 4731 (2019).

    PubMed  PubMed Central  Google Scholar 

  121. Smer-Barreto, V. et al. Discovery of senolytics using machine learning. Nat. Commun. 14, 3445 (2023).

    PubMed  PubMed Central  Google Scholar 

  122. Therien, A. G. & Blostein, R. Mechanisms of sodium pump regulation. Am. J. Physiol. Cell Physiol. 279, C541–C566 (2000).

    PubMed  Google Scholar 

  123. Russo, G. L. et al. Mechanisms of aging and potential role of selected polyphenols in extending healthspan. Biochem. Pharmacol. 173, 113719 (2020).

    PubMed  Google Scholar 

  124. Zhu, Y. et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14, 644–658 (2015). This article provides the first description of the combination of D + Q as senolytics.

    PubMed  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  126. Justice, J. N. et al. Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study. EBioMedicine 40, 554–563 (2019).

    PubMed  PubMed Central  Google Scholar 

  127. Hickson, L. J. et al. Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of dasatinib plus quercetin in individuals with diabetic kidney disease. EBioMedicine 47, 446–456 (2019). First in human study using D + Q as a senolytic therapy.

    PubMed  PubMed Central  Google Scholar 

  128. Yousefzadeh, M. J. et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine 36, 18–28 (2018).

    PubMed  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  130. Ovadya, Y. et al. Impaired immune surveillance accelerates accumulation of senescent cells and aging. Nat. Commun. 9, 5435 (2018).

    PubMed  PubMed Central  Google Scholar 

  131. Prieto, L. I., Sturmlechner, I., Goronzy, J. J. & Baker, D. J. Senescent cells as thermostats of antitumor immunity. Sci. Transl. Med. 15, eadg7291 (2023).

    PubMed  PubMed Central  Google Scholar 

  132. Hasegawa, T. et al. Cytotoxic CD4+ T cells eliminate senescent cells by targeting cytomegalovirus antigen. Cell 186, 1417–1431.e20 (2023).

    PubMed  Google Scholar 

  133. Chen, H. A. et al. Senescence rewires microenvironment sensing to facilitate antitumor immunity. Cancer Discov. 13, 432–453 (2023).

    PubMed  Google Scholar 

  134. Shahbandi, A. et al. Breast cancer cells survive chemotherapy by activating targetable immune-modulatory programs characterized by PD-L1 or CD80. Nat. Cancer 3, 1513–1533 (2022).

    PubMed  PubMed Central  Google Scholar 

  135. Pereira, B. I. et al. Senescent cells evade immune clearance via HLA-E-mediated NK and CD8+ T cell inhibition. Nat. Commun. 10, 2387 (2019).

    PubMed  PubMed Central  Google Scholar 

  136. Munoz, D. P. et al. Targetable mechanisms driving immunoevasion of persistent senescent cells link chemotherapy-resistant cancer to aging. JCI Insight 5, e124716 (2019).

    PubMed  Google Scholar 

  137. Robert, C. A decade of immune-checkpoint inhibitors in cancer therapy. Nat. Commun. 11, 3801 (2020).

    PubMed  PubMed Central  Google Scholar 

  138. Arora, S. et al. Invariant natural killer T cells coordinate removal of senescent cells. Med 2, 938–950 (2021).

    PubMed  Google Scholar 

  139. Kim, K. M. et al. Identification of senescent cell surface targetable protein DPP4. Genes. Dev. 31, 1529–1534 (2017).

    PubMed  PubMed Central  Google Scholar 

  140. Amor, C. et al. Senolytic CAR T cells reverse senescence-associated pathologies. Nature https://doi.org/10.1038/s41586-020-2403-9 (2020). This study is the first to report the use of senolytic CAR-T cells.

  141. Poblocka, M. et al. Targeted clearance of senescent cells using an antibody–drug conjugate against a specific membrane marker. Sci. Rep. 11, 20358 (2021).

    PubMed  PubMed Central  Google Scholar 

  142. Suda, M. et al. Glycoprotein nonmetastatic melanoma protein B regulates lysosomal integrity and lifespan of senescent cells. Sci. Rep. 12, 6522 (2022).

    PubMed  PubMed Central  Google Scholar 

  143. Sagiv, A. et al. NKG2D ligands mediate immunosurveillance of senescent cells. Aging 8, 328–344 (2016).

    PubMed  PubMed Central  Google Scholar 

  144. Yang, D. et al. NKG2D-CAR T cells eliminate senescent cells in aged mice and nonhuman primates. Sci. Transl. Med. 15, eadd1951 (2023).

    PubMed  Google Scholar 

  145. Yoshida, S. et al. The CD153 vaccine is a senotherapeutic option for preventing the accumulation of senescent T cells in mice. Nat. Commun. 11, 2482 (2020).

    PubMed  PubMed Central  Google Scholar 

  146. Marin, I. et al. Cellular senescence is immunogenic and promotes antitumor immunity. Cancer Discov. 13, 410–431 (2023).

    PubMed  Google Scholar 

  147. Birch, J. & Gil, J. Senescence and the SASP: many therapeutic avenues. Genes. Dev. 34, 1565–1576 (2020).

    PubMed  PubMed Central  Google Scholar 

  148. Gluck, S. et al. Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence. Nat. Cell Biol. 19, 1061–1070 (2017).

    PubMed  PubMed Central  Google Scholar 

  149. Dou, Z. et al. Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature 550, 402–406 (2017). Together with Gluck et al. (2017), this work highlights the role of cGAS–STING on SASP and senescence regulation.

    PubMed  PubMed Central  Google Scholar 

  150. Vizioli, M. G. et al. Mitochondria-to-nucleus retrograde signaling drives formation of cytoplasmic chromatin and inflammation in senescence. Genes. Dev. 34, 428–445 (2020).

    PubMed  PubMed Central  Google Scholar 

  151. 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).

    PubMed  Google Scholar 

  152. 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).

    PubMed  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  154. Kuilman, T. et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133, 1019–1031 (2008).

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  156. Gulen, M. F. et al. cGAS–STING drives ageing-related inflammation and neurodegeneration. Nature 620, 374–380 (2023).

    PubMed  PubMed Central  Google Scholar 

  157. Xu, M. et al. JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age. Proc. Natl Acad. Sci. USA 112, E6301–E6310 (2015).

    PubMed  PubMed Central  Google Scholar 

  158. Georgilis, A. et al. PTBP1-mediated alternative splicing regulates the inflammatory secretome and the pro-tumorigenic effects of senescent cells. Cancer Cell 34, 85–102.e9 (2018).

    PubMed  PubMed Central  Google Scholar 

  159. Bird, T. G. et al. TGFβ inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence. Sci. Transl. Med. 10, eaan1230 (2018).

    PubMed  PubMed Central  Google Scholar 

  160. Widjaja, A. A. et al. Inhibition of IL-11 signalling extends mammalian healthspan and lifespan. Nature 632, 157–165 (2024).

    PubMed  PubMed Central  Google Scholar 

  161. Ogata, A., Kato, Y., Higa, S. & Yoshizaki, K. IL-6 inhibitor for the treatment of rheumatoid arthritis: a comprehensive review. Mod. Rheumatol. 29, 258–267 (2019).

    PubMed  Google Scholar 

  162. Mariette, X. et al. Effectiveness of tocilizumab in patients hospitalized with COVID-19: a follow-up of the CORIMUNO-TOCI-1 randomized clinical trial. JAMA Intern. Med. 181, 1241–1243 (2021).

    PubMed  PubMed Central  Google Scholar 

  163. Schmitt, C. A. et al. COVID-19 and cellular senescence. Nat. Rev. Immunol. 23, 251–263 (2023).

    PubMed  Google Scholar 

  164. Del Rey, M. J. et al. Senescent synovial fibroblasts accumulate prematurely in rheumatoid arthritis tissues and display an enhanced inflammatory phenotype. Immun. Ageing 16, 29 (2019).

    PubMed  PubMed Central  Google Scholar 

  165. Basisty, N. et al. A proteomic atlas of senescence-associated secretomes for aging biomarker development. PLoS Biol. 18, e3000599 (2020).

    PubMed  PubMed Central  Google Scholar 

  166. Hoare, M. et al. NOTCH1 mediates a switch between two distinct secretomes during senescence. Nat. Cell Biol. 18, 979–992 (2016).

    PubMed  PubMed Central  Google Scholar 

  167. Toso, A. et al. Enhancing chemotherapy efficacy in Pten-deficient prostate tumors by activating the senescence-associated antitumor immunity. Cell Rep. 9, 75–89 (2014).

    PubMed  Google Scholar 

  168. Franceschi, C. et al. Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech. Ageing Dev. 128, 92–105 (2007).

    PubMed  Google Scholar 

  169. Ruscetti, M. et al. NK cell-mediated cytotoxicity contributes to tumor control by a cytostatic drug combination. Science 362, 1416–1422 (2018).

    PubMed  PubMed Central  Google Scholar 

  170. Ruscetti, M. et al. Senescence-induced vascular remodeling creates therapeutic vulnerabilities in pancreas cancer. Cell 181, 424–441.e21 (2020).

    PubMed  PubMed Central  Google Scholar 

  171. Chibaya, L. et al. EZH2 inhibition remodels the inflammatory senescence-associated secretory phenotype to potentiate pancreatic cancer immune surveillance. Nat. Cancer 4, 872–892 (2023).

    PubMed  PubMed Central  Google Scholar 

  172. Blagosklonny, M. V. Rapamycin, proliferation and geroconversion to senescence. Cell Cycle 17, 2655–2665 (2018).

    PubMed  PubMed Central  Google Scholar 

  173. Fumagalli, M. et al. Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat. Cell Biol. 14, 355–365 (2012).

    PubMed  PubMed Central  Google Scholar 

  174. Aguado, J. et al. Inhibition of DNA damage response at telomeres improves the detrimental phenotypes of Hutchinson–Gilford progeria syndrome. Nat. Commun. 10, 4990 (2019).

    PubMed  PubMed Central  Google Scholar 

  175. Bousset, L. & Gil, J. Targeting senescence as an anticancer therapy. Mol. Oncol. 16, 3855–3880 (2022).

    PubMed  PubMed Central  Google Scholar 

  176. Ou, H. L. et al. Cellular senescence in cancer: from mechanisms to detection. Mol. Oncol. 15, 2634–2671 (2021).

    PubMed  Google Scholar 

  177. Chambers, C. R., Ritchie, S., Pereira, B. A. & Timpson, P. Overcoming the senescence-associated secretory phenotype (SASP): a complex mechanism of resistance in the treatment of cancer. Mol. Oncol. 15, 3242–3255 (2021).

    PubMed  PubMed Central  Google Scholar 

  178. Wang, L. & Bernards, R. Taking advantage of drug resistance, a new approach in the war on cancer. Front. Med. 12, 490–495 (2018).

    PubMed  Google Scholar 

  179. Fleury, H. et al. Exploiting interconnected synthetic lethal interactions between PARP inhibition and cancer cell reversible senescence. Nat. Commun. 10, 2556 (2019).

    PubMed  PubMed Central  Google Scholar 

  180. Jochems, F. et al. The cancer SENESCopedia: a delineation of cancer cell senescence. Cell Rep. 36, 109441 (2021).

    PubMed  PubMed Central  Google Scholar 

  181. Kolodkin-Gal, D. et al. Senolytic elimination of Cox2-expressing senescent cells inhibits the growth of premalignant pancreatic lesions. Gut 71, 345–355 (2021).

    PubMed  Google Scholar 

  182. Alvarez-Fernandez, M. & Malumbres, M. Mechanisms of sensitivity and resistance to CDK4/6 inhibition. Cancer Cell 37, 514–529 (2020).

    PubMed  Google Scholar 

  183. Wang, L. et al. High-throughput functional genetic and compound screens identify targets for senescence induction in cancer. Cell Rep. 21, 773–783 (2017).

    PubMed  Google Scholar 

  184. Baell, J. B. et al. Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth. Nature 560, 253–257 (2018).

    PubMed  Google Scholar 

  185. Heckenbach, I. et al. Nuclear morphology is a deep learning biomarker of cellular senescence. Nat. Aging 2, 742–755 (2022).

    PubMed  PubMed Central  Google Scholar 

  186. Kusumoto, D. et al. Anti-senescent drug screening by deep learning-based morphology senescence scoring. Nat. Commun. 12, 257 (2021).

    PubMed  PubMed Central  Google Scholar 

  187. Duran, I. et al. Detection of senescence using machine learning algorithms based on nuclear features. Nat. Commun. 15, 1041 (2024). Together with Heckenbach et al. (2022) and Kusumoto et al. (2021), this work reports the use of a machine learning analysis of morphological parameters to detect SnCs.

    PubMed  PubMed Central  Google Scholar 

  188. Cui, W., Liu, L., Kodibagkar, V. D. & Mason, R. P. S-Gal, a novel 1H MRI reporter for β-galactosidase. Magn. Reson. Med. 64, 65–71 (2010).

    PubMed  PubMed Central  Google Scholar 

  189. Schafer, M. J. et al. The senescence-associated secretome as an indicator of age and medical risk. JCI Insight 5, e133668 (2020).

    PubMed  PubMed Central  Google Scholar 

  190. Wiley, C. D. et al. Oxylipin biosynthesis reinforces cellular senescence and allows detection of senolysis. Cell Metab. 33, 1124–1136.e5 (2021). This article provides a description of a biomarker of senolysis that can be detected in the blood.

    PubMed  PubMed Central  Google Scholar 

  191. Farr, J. N. et al. Local senolysis in aged mice only partially replicates the benefits of systemic senolysis. J. Clin. Invest. 133, e162519 (2023).

    PubMed  PubMed Central  Google Scholar 

  192. Nambiar, A. et al. Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability. EBioMedicine 90, 104481 (2023).

    PubMed  PubMed Central  Google Scholar 

  193. Hashimoto, M. et al. Elimination of p19ARF-expressing cells enhances pulmonary function in mice. JCI Insight 1, e87732 (2016).

    PubMed  PubMed Central  Google Scholar 

  194. Chandra, A. et al. Targeted clearance of p21- but not p16-positive senescent cells prevents radiation-induced osteoporosis and increased marrow adiposity. Aging Cell 21, e13602 (2022).

    PubMed  PubMed Central  Google Scholar 

  195. Ohtani, N., Yamakoshi, K., Takahashi, A. & Hara, E. Real-time in vivo imaging of p16 gene expression: a new approach to study senescence stress signaling in living animals. Cell Div. 5, 1 (2010).

    PubMed  PubMed Central  Google Scholar 

  196. Ohtani, N. et al. Visualizing the dynamics of p21Waf1/Cip1 cyclin-dependent kinase inhibitor expression in living animals. Proc. Natl Acad. Sci. USA 104, 15034–15039 (2007).

    PubMed  PubMed Central  Google Scholar 

  197. Liu, J. Y. et al. Cells exhibiting strong p16INK4a promoter activation in vivo display features of senescence. Proc. Natl Acad. Sci. USA 116, 2603–2611 (2019).

    PubMed  PubMed Central  Google Scholar 

  198. Hori, N. et al. Shaving black fur uncovers hidden issues in p16-3MR mice. Preprint at bioRxiv https://doi.org/10.1101/2024.06.24.600181 (2024).

Download references

Acknowledgements

Figures have been partially generated with Biorender (Biorender.com) and Smart Servier Medical ART (https://smart.servier.com). For open access, the author has applied a Creative Commons Attribution (CC BY) licence. Core support from the Medical Research Council (MRC) (MC_U120085810) and a grant from Cancer Research UK (CRUK) (C15075/A28647) funded research in the Gil laboratory.

Author information

Authors and Affiliations

  1. Senescence Group, MRC Laboratory of Medical Sciences (LMS), London, UK

    Domhnall McHugh, Imanol Durán & Jesús Gil

  2. Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, UK

    Domhnall McHugh, Imanol Durán & Jesús Gil

Authors
  1. Domhnall McHugh
    View author publications

    Search author on:PubMed Google Scholar

  2. Imanol Durán
    View author publications

    Search author on:PubMed Google Scholar

  3. Jesús Gil
    View author publications

    Search author on:PubMed Google Scholar

Contributions

All authors researched data for the article, contributed to the discussion of the content and organization of the review and wrote the article.

Corresponding author

Correspondence to Jesús Gil.

Ethics declarations

Competing interests

J.G. has acted as a consultant for Unity Biotechnology, Geras Bio, Myricx Pharma Ltd. and Merck KGaA; owns equity in Geras Bio and share options in Myricx Pharma Ltd; is a named inventor in Medical Research Council (MRC) patents related to senolytic therapies; and has in the past received funding from Pfizer and Unity Biotechnology to work on senolytics. D.M. and J.G. are named inventors in an Imperial College patent related to senolytic therapies. I.D. declares no competing interest.

Peer review

Peer review information

Nature Reviews Drug Discovery thanks Christopher Wiley and the other, anonymous, reviewer for their contribution to the peer review of this work.

Additional information

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

Glossary

Apical ectodermal ridge

A structure formed by a thickening of the ectoderm around the distal part of limb buds during development.

Cardiac glycosides

(CGs). A family of natural compounds found in plants and amphibians that inhibit Na+/K+-ATPases.

Coat protein complex I

(COPI). A protein complex for which one of its main functions is the formation of vesicles that transport proteins from the Golgi to the endoplasmic reticulum.

DNA segments with chromatin alterations reinforcing senescence

(DNA-SCARS). Nuclear structures present in senescent cells (SnCs) with persistent DNA damage.

INK-ATTAC mice

A mouse model in which a chimeric form of caspase 8 is expressed under the INK4a promoter, making possible the selective elimination of senescent cells (SnCs) expressing high levels of p16INK4a upon addition of a drug (AP20187) that activates the chimeric caspase 8 construct. INK refers to INK4a (encoding for p16INK4a), ATTAC is short for apoptosis through targeted activation of caspase.

Invariant natural killer T cells

A class of lymphocytes expressing T cell receptors that are activated by lipid antigens.

Langerhans cell histiocytosis

A rare neoplasia caused by the abnormal accumulation of a type of immune cells called Langerhans cells.

Mesoporous silica nanoparticles

A type of silica-based nanostructures with well-defined pore diameters (2–50 nm, in the ‘mesoscale’) that can be loaded with drugs or cargo which can be released in a controlled fashion if functionalized.

Multimorbidities

Co-occurrence of two or more chronic illnesses, more common in aged individuals.

Myeloid-derived suppressor cells

(MDSCs). Myeloid cells that inhibit the activity of natural killer cells (NK cells) and CD8+ T cells.

Non-homologous end joining

A mechanism to repair double-strand breaks in the DNA through direct ligation of the break ends and without the need for a homologous DNA template.

Preneoplastic cells

Cells harbouring oncogenic lesions which have a higher risk of becoming transformed.

Progeroid mice

A mouse model (such as BubR1H/H mice) that displays characteristics associated with ageing at an early age.

Proteolysis-targeting chimaera

(PROTAC). A class of drugs that causes the selective degradation of their targets.

Senescence-associated β-galactosidase

(SA-β-gal). Lysosomal β-galactosidase activity that is assayed at an acid pH and that is used as a senescence marker.

Surfaceome

A collective name which is used to refer to the surface proteins expressed by a cell.

Telomeric attrition

Progressive shortening of the chromosome ends (telomeres) that happens after every cell division as a consequence of the ‘end replication problem’.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

McHugh, D., Durán, I. & Gil, J. Senescence as a therapeutic target in cancer and age-related diseases. Nat Rev Drug Discov 24, 57–71 (2025). https://doi.org/10.1038/s41573-024-01074-4

Download citation

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41573-024-01074-4

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer