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Cellular senescence and senolytics: the path to the clinic

Nature Medicine volume 28, pages 1556–1568 (2022) Cite this article

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Abstract

Interlinked and fundamental aging processes appear to be a root-cause contributor to many disorders and diseases. One such process is cellular senescence, which entails a state of cell cycle arrest in response to damaging stimuli. Senescent cells can arise throughout the lifespan and, if persistent, can have deleterious effects on tissue function due to the many proteins they secrete. In preclinical models, interventions targeting those senescent cells that are persistent and cause tissue damage have been shown to delay, prevent or alleviate multiple disorders. In line with this, the discovery of small-molecule senolytic drugs that selectively clear senescent cells has led to promising strategies for preventing or treating multiple diseases and age-related conditions in humans. In this Review, we outline the rationale for senescent cells as a therapeutic target for disorders across the lifespan and discuss the most promising strategies—including recent and ongoing clinical trials—for translating small-molecule senolytics and other senescence-targeting interventions into clinical use.

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Fig. 1: Senescence-associated secretory phenotype.
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Fig. 2: The threshold theory of senescent cell accumulation.
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Fig. 3: First- and second-generation senolytic strategies.
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Acknowledgements

This work was supported by the US National Institutes of Health (grants R37AG013925, R33AG061456, R01AG072301, R01AG061414, P01AG062413 and UH3AG056933), the Connor Fund, Robert J. and Theresa W. Ryan and the Noaber Foundation.

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  1. Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA

    Selim Chaib, Tamar Tchkonia & James L. Kirkland

  2. Division of General Internal Medicine, Department of Medicine, Mayo Clinic, Rochester, MN, USA

    James L. Kirkland

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J.L.K. conceptualized this Review. All authors contributed to the writing and approved the submitted version of the manuscript. S.C. created the figures using BioRender.com.

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T.T. and J.L.K. have a financial interest related to this research, including patents and pending patents covering senolytic drugs and their uses that are held by Mayo Clinic. S.C. has received royalties from Rejuveron Senescence Therapeutics. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and was conducted in compliance with the Mayo Clinic’s conflict of interest policies.

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Chaib, S., Tchkonia, T. & Kirkland, J.L. Cellular senescence and senolytics: the path to the clinic. Nat Med 28, 1556–1568 (2022). https://doi.org/10.1038/s41591-022-01923-y

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