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Translating cellular senescence research into clinical practice for metabolic disease

Nature Reviews Endocrinology (2025)Cite this article

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Abstract

Translational research on cellular senescence has led to numerous early-phase clinical trials targeting senescent cells to treat, prevent or alleviate multiple disorders and diseases, including metabolic diseases and their comorbidities. Cellular senescence is a cell fate that occurs in response to stressors, including metabolic disruptions, and is one of the hallmarks (or pillars) of ageing. In their senescent state, cells cease proliferation and can develop a senescence-associated secretory and metabolic phenotype that contributes to the pathogenesis of metabolic dysfunction associated with obesity and ageing. Metabolic stress, which is central to the development of metabolic diseases, can trigger cellular senescence, thereby enabling a vicious cycle that exacerbates metabolic dysfunction. Therapies targeting senescent cells (senotherapeutics), either alone or in combination with other gerotherapies or lifestyle interventions, hold great promise for addressing the ongoing obesity epidemic and the need for improved therapies to prevent and treat metabolic diseases and their complications and comorbidities. In this Review, we discuss novel senotherapeutics, including challenges related to the translation of these therapies and the need to establish gerodiagnostic biomarkers to track the elimination of senescent cells, define eligibility and measure efficacy, as well as considerations for clinical trial design and execution.

Key points

  • Cellular senescence is a fundamental ageing process that seems to contribute to the pathogenesis of many chronic diseases, including metabolic diseases.

  • Lifestyle and pharmacological interventions that affect metabolic disorders can prevent senescent cell accumulation or modulate their secretory phenotype.

  • Elimination of senescent cells with senolytic drugs or inhibition of the senescence-associated secretory phenotype have shown promise for preventing, alleviating or delaying metabolic diseases and associated comorbidities in preclinical models.

  • Senotherapies are a potentially viable intervention for treatment of metabolic diseases.

  • Early-phase clinical trials are evaluating the safety and tolerability of senolytic drugs, along with monitoring target engagement (the clearance of senescent cells) across multiple age-related diseases.

  • The development of gerodiagnostic biomarkers that target fundamental ageing processes will be critical for identifying individuals who will benefit the most from senolytic therapies and facilitate individualized approaches for treatment of metabolic diseases.

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Fig. 1: Pathogenic loop of metabolic insults and cellular senescence.
Fig. 2: Senotherapeutic strategies and their targets.

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Acknowledgements

The authors acknowledge the support of the National Institutes of Health (grants R37AG13925, R33AG61456, R01AG72301, R01AG61414, R01AG69690, U54AG75941, R01AG89711 and R01AG75684), the Hevolution Foundation (HF-GRO-23-1199148-3), the Connor Fund, Robert J. and Theresa W. Ryan, and the Noaber Foundation. The authors are grateful to T. Evans, senior program coordinator of the Translational Geoscience Network, for contributing to clinical trials of senolytics.

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Author notes

  1. These authors contributed equally: Selim Chaib, Allyson K. Palmer.

Authors and Affiliations

  1. Center for Advanced Gerotherapeutics, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Selim Chaib, James L. Kirkland & Tamara Tchkonia

  2. Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Selim Chaib, Nicolas Musi, James L. Kirkland & Tamara Tchkonia

  3. Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA

    Allyson K. Palmer

  4. Division of Hospital Internal Medicine, Department of Medicine, Mayo Clinic, Rochester, MN, USA

    Allyson K. Palmer

  5. Department of Dermatology, Mayo Clinic, Rochester, MN, USA

    Saranya P. Wyles

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Contributions

S.C. and A.K.P. contributed to all aspects of the article. S.P.W. and N.M. contributed to writing the article and to reviewing and/or editing the manuscript before submission. J.L.K. and T.T. contributed to discussion of the content, writing the article and to reviewing and/or editing the manuscript before submission.

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Correspondence to Tamara Tchkonia.

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Competing interests

T.T., A.K.P. and J.L.K. have a financial interest related to this article, including patents and pending patents covering senolytic drugs and their uses. S.C. holds patents or pending patents on PDL2 at Mayo Clinic and Spanish National Cancer Research Center, some of which have been licensed to Rejuveron Senescence Therapeutics. The other authors declare no competing interests.

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Nature Reviews Endocrinology thanks Cristina Aguayo-Mazzucato, Ippei Shimizu and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Chaib, S., Palmer, A.K., Wyles, S.P. et al. Translating cellular senescence research into clinical practice for metabolic disease. Nat Rev Endocrinol (2025). https://doi.org/10.1038/s41574-025-01187-9

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