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Cellular senescence as a possible link between prostate diseases of the ageing male

Nature Reviews Urology volume 18, pages 597–610 (2021)Cite this article

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Abstract

Senescent cells accumulate with age in all tissues. Although senescent cells undergo cell-cycle arrest, these cells remain metabolically active and their secretome — known as the senescence-associated secretory phenotype — is responsible for a systemic pro-inflammatory state, which contributes to an inflammatory microenvironment. Senescent cells can be found in the ageing prostate and the senescence-associated secretory phenotype and can be linked to BPH and prostate cancer. Indeed, a number of signalling pathways provide biological plausibility for the role of senescence in both BPH and prostate cancer, although proving causality is difficult. The theory of senescence as a mechanism for prostate disease has a number of clinical implications and could offer opportunities for targeting in the future.

Key points

  • BPH and prostate cancer are two common disorders affecting the prostate and both share an increased incidence with advancing age.

  • Ageing, along with other sources of cellular damage (infection, toxins, chemical or physical injury), results in cellular senescence and the accumulation of senescent cells in tissues.

  • Senescent cells, although unable to replicate, remain metabolically active and secrete a raft of inflammatory mediators, known as the senescence-associated secretory phenotype (SASP).

  • Senescent cells have been detected using senescence markers in almost all human samples of BPH, and the role of several components of the SASP has been established in BPH initiation and progression.

  • The role of cellular senescence in prostate cancer is less clearly established, and senescence seems to act mainly through the influence of the senescent stroma on adjacent epithelial cells, favouring cancer initiation, progression and metastasis.

  • The demonstration of the role of senescence in both age-related prostatic diseases presents new therapeutic opportunities with treatments aimed at removing senescent cells (senolytics) and/or targeting components of the SASP (SASP inhibitors or senomorphics).

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Fig. 1: Differences between the young and ageing hypertrophied prostate.
Fig. 2: Chaotic architecture of the transition zone in the ageing hypertrophied prostate.
Fig. 3: The implications of senescent cells in BPH and prostate cancer.
Fig. 4: Key signal transducers activated by the senescence-associated secretory phenotype.

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Acknowledgements

G.F. receives funding from the Fondation de France and the European Urology Scholarship Program. V.S. is supported by an MRC Clinical Research Training Fellowship (MR/S005897/1), the Mason Medical Research Foundation (project number: 558866) and acknowledges previous support from The Alan Turing Institute (EPSRC grant EP/N510129/1), the EACR (EACR Travel Fellowship) and UCL (Bogue Fellowship). E.S.C. is funded by a Barts Charity Lectureship (grant MGU045). S.H. is supported by a Movember-funded Prostate Cancer UK fellowship, TLD-PF16-004. A.N.A. is supported by the Medical Research Council (MR/P00184X/1) and an MRC Grand Challenge in Experimental Medicine Grant (MR/M003833/1). M.E. receives research support from the United Kingdom’s National Institute of Health Research (NIHR) UCLH/UCL Biomedical Centre. He was conferred NIHR Senior Investigator status in 2015.

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Authors and Affiliations

  1. UCL Division of Surgery & Interventional Science, University College London, London, UK

    Gaelle Fiard, Vasilis Stavrinides, Susan Heavey & Mark Emberton

  2. Department of Urology, Grenoble Alpes University Hospital, Grenoble, France

    Gaelle Fiard

  3. Univ. Grenoble Alpes, CNRS, Grenoble INP, TIMC-IMAG, Grenoble, France

    Gaelle Fiard

  4. Centre for Immunobiology, Blizard Institute, Queen Mary University of London, London, UK

    Emma S. Chambers

  5. Department of Pathology, University College London Hospitals NHS Foundation Trust, London, UK

    Alex Freeman & Rhys Ball

  6. Division of Medicine, The Rayne Building, University College London, London, UK

    Arne N. Akbar

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G.F., V.S., E.S.C. and S.H. researched data for the article. All authors contributed substantially to discussion of the content. G.F., V.S., E.S.C., S.H. and M.E. wrote the article. All authors reviewed and/or edited the manuscript before submission.

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Fiard, G., Stavrinides, V., Chambers, E.S. et al. Cellular senescence as a possible link between prostate diseases of the ageing male. Nat Rev Urol 18, 597–610 (2021). https://doi.org/10.1038/s41585-021-00496-8

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