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Adipocyte and Cell Biology

Cellular senescence and its role in white adipose tissue

International Journal of Obesity volume 45, pages 934–943 (2021)Cite this article

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Abstract

Cell senescence is defined as a state of irreversible cell cycle arrest combined with DNA damage and the induction of a senescence-associated secretory phenotype (SASP). This includes increased secretion of many inflammatory agents, proteases, miRNA’s, and others. Cell senescence has been widely studied in oncogenesis and has generally been considered to be protective, due to cell cycle arrest and the inhibition of proliferation. Cell senescence is also associated with ageing and extensive experimental data support its role in generating the ageing-associated phenotype. Senescent cells can also influence proximal “healthy” cells through SASPs and, e.g., inhibit normal development of progenitor/stem cells, thereby preventing tissue replacement of dying cells and reducing organ functions. Recent evidence demonstrates that SASPs may also play important roles in several chronic diseases including diabetes and cardiovascular disease. White adipose tissue (WAT) cells are highly susceptible to becoming senescent both with ageing but also with obesity and type 2 diabetes, independently of chronological age. WAT senescence is associated with inappropriate expansion (hypertrophy) of adipocytes, insulin resistance, and dyslipidemia. Major efforts have been made to identify approaches to delete senescent cells including the use of “senolytic” compounds. The most established senolytic treatment to date is the combination of dasatinib, an antagonist of the SRC family of kinases, and the antioxidant quercetin. This combination reduces cell senescence and improves chronic disorders in experimental animal models. Although only small and short-term studies have been performed in man, no severe adverse effects have been reported. Hopefully, these or other senolytic agents may provide novel ways to prevent and treat different chronic diseases in man. Here we review the current knowledge on cellular senescence in both murine and human studies. We also discuss the pathophysiological role of this process and the potential therapeutic relevance of targeting senescence selectively in WAT.

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Fig. 1: Schematic representation of a DNA damage response (DDR) induced cell cycle arrest.
Fig. 2: Schematic of mechanisms inducing senescence.

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Acknowledgements

The authors are supported by grants from the Swedish Research Council, Diabetes Research Program at Karolinska Institutet, CIMED, the ERC SyG SPHERES, Novo Nordisk Foundation (the Tripartite Immuno-metabolism Consortium Grant NNF15CC0018486, the MSAM consortium NNF15SA0018346, and Grant NNF20OC0063541), the Swedish Diabetes Foundation, the Knut and Alice Wallenberg Foundation, the Stockholm County Council and the West Sweden ALF foundation.

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  1. The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

    Ulf Smith

  2. Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden

    Qian Li & Kirsty L. Spalding

  3. Department of Medicine, Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

    Mikael Rydén

  4. Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre (KI/AZ ICMC), Department of Medicine, Karolinska Institutet, Stockholm, Sweden

    Kirsty L. Spalding

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Smith, U., Li, Q., Rydén, M. et al. Cellular senescence and its role in white adipose tissue. Int J Obes 45, 934–943 (2021). https://doi.org/10.1038/s41366-021-00757-x

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