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Cellular senescence: the good, the bad and the unknown

Nature Reviews Nephrology volume 18, pages 611–627 (2022)Cite this article

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Abstract

Cellular senescence is a ubiquitous process with roles in tissue remodelling, including wound repair and embryogenesis. However, prolonged senescence can be maladaptive, leading to cancer development and age-related diseases. Cellular senescence involves cell-cycle arrest and the release of inflammatory cytokines with autocrine, paracrine and endocrine activities. Senescent cells also exhibit morphological alterations, including flattened cell bodies, vacuolization and granularity in the cytoplasm and abnormal organelles. Several biomarkers of cellular senescence have been identified, including SA-βgal, p16 and p21; however, few markers have high sensitivity and specificity. In addition to driving ageing, senescence of immune and parenchymal cells contributes to the development of a variety of diseases and metabolic disorders. In the kidney, senescence might have beneficial roles during development and recovery from injury, but can also contribute to the progression of acute kidney injury and chronic kidney disease. Therapies that target senescence, including senolytic and senomorphic drugs, stem cell therapies and other interventions, have been shown to extend lifespan and reduce tissue injury in various animal models. Early clinical trials confirm that senotherapeutic approaches could be beneficial in human disease. However, larger clinical trials are needed to translate these approaches to patient care.

Key points

  • Cellular senescence regulates physiological and homeostatic processes, particularly during embryonic development and wound healing, but can also be a pathological process that contributes to ageing, various diseases and metabolic disorders.

  • Senescent cells are characterized by morphological alterations including large, flat bodies and organelle abnormalities, as well as loss of physiological functions, an inability to proliferate and the senescence-associated secretory phenotype.

  • SABG, p21 and p16 are the most commonly used senescence markers but have limitations; novel non-invasive approaches are needed to detect cellular senescence with high sensitivity and specificity in vitro.

  • Cellular senescence is involved in the pathogenesis of chronic kidney disease and acute kidney injury, but also seems to have a protective role in the early stages of acute kidney injury.

  • Senescence-targeting interventions, including senolytic drugs conjugated to antibodies against β2-microglobulin, chimeric antigen receptor T cells and anti-ageing vaccines, show promise for clinical application.

  • Clinical trials are needed to assess the safety and efficacy of senotherapeutic approaches, optimize treatment regimens and develop more individualized and standardized treatment strategies.

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Fig. 1: Mechanisms of cellular senescence and the SASP.
Fig. 2: Cellular senescence in cancer.
Fig. 3: Cellular senescence in kidney diseases.
Fig. 4: Mechanisms of cellular senescence in chronic kidney disease.

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Acknowledgements

The authors’ work was supported by National Institutes of Health grant numbers DK120292, DK122734, AG062104, AG013925 and AG61456, the Connor Fund, Robert P. and Arlene R. Kogod, Robert J. and Theresa W. Ryan, and the Noaber Foundation.

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Authors and Affiliations

  1. Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA

    Weijun Huang, Alfonso Eirin & Lilach O. Lerman

  2. Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China

    Weijun Huang

  3. Division of Nephrology and Hypertension, Mayo Clinic, Jacksonville, FL, USA

    LaTonya J. Hickson

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

    James L. Kirkland

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  1. Weijun Huang
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  2. LaTonya J. Hickson
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Contributions

W.H. researched the data for the article and wrote the text. W.H. and L.O.L contributed substantially to discussion of the content. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to Lilach O. Lerman.

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Competing interests

L.O.L. is an adviser to AstraZeneca, CureSpec, Beren, Ribocure Pharmaceuticals and Butterfly Biosciences. Patents on senolytic drugs and their uses are held by the Mayo Clinic. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and was conducted in compliance with Mayo Clinic Conflict of Interest policies. The other authors declare no conflicts of interest.

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Glossary

DREAM complex

A multisubunit complex formed by the assembly of p130 and p107 with their dimerization partner, E2F4/5, and a multi-vulva class-B core complex.

Somatic hypermutation

A programmed process of adaptation to new foreign elements (such as microbes) whereby changes are introduced to the nucleotide sequences of immunoglobulin genes during B cell development.

Efferocytosis

The process by which apoptotic cells are removed by phagocytic cells.

Ramified

Used to describe cells that have long branch-like processes.

Geroprotective protein

A protein that has anti-ageing effects.

Radio-electric asymmetric conveyer technology

A technology delivering very low-intensity radio-electric emission to generate microcurrents in tissues or culture media and thereby produce biological effects.

Metabolic memory

The durable effect of prior hyperglycaemia on the initiation and progression of diabetic complications.

Tenocytes

Elongated fibroblasts and fibrocytes that reside between collagen fibres.

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Huang, W., Hickson, L.J., Eirin, A. et al. Cellular senescence: the good, the bad and the unknown. Nat Rev Nephrol 18, 611–627 (2022). https://doi.org/10.1038/s41581-022-00601-z

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