Letter | Published:

Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders

Nature volume 479, pages 232236 (10 November 2011) | Download Citation


Advanced age is the main risk factor for most chronic diseases and functional deficits in humans, but the fundamental mechanisms that drive ageing remain largely unknown, impeding the development of interventions that might delay or prevent age-related disorders and maximize healthy lifespan. Cellular senescence, which halts the proliferation of damaged or dysfunctional cells, is an important mechanism to constrain the malignant progression of tumour cells1,2. Senescent cells accumulate in various tissues and organs with ageing3 and have been hypothesized to disrupt tissue structure and function because of the components they secrete4,5. However, whether senescent cells are causally implicated in age-related dysfunction and whether their removal is beneficial has remained unknown. To address these fundamental questions, we made use of a biomarker for senescence, p16Ink4a, to design a novel transgene, INK-ATTAC, for inducible elimination of p16Ink4a-positive senescent cells upon administration of a drug. Here we show that in the BubR1 progeroid mouse background, INK-ATTAC removes p16Ink4a-positive senescent cells upon drug treatment. In tissues—such as adipose tissue, skeletal muscle and eye—in which p16Ink4a contributes to the acquisition of age-related pathologies, life-long removal of p16Ink4a-expressing cells delayed onset of these phenotypes. Furthermore, late-life clearance attenuated progression of already established age-related disorders. These data indicate that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan.

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We thank W. Zhou, D. Norris, T. Mann, U. Moedder, T. Pirtskhalava and S. Yamada for assistance; S. Khosla, T. von Zglinicki, L. Malureanu, R. Ricke and P. Galardy, and members of the J.M.v.D. laboratory for helpful discussions; and P. Scherer for the gift of the aP2-ATTAC plasmid. This work was supported by the Ellison Medical Foundation (J.M.v.D.), the Noaber Foundation (J.M.v.D. and J.L.K.), the Robert and Arlene Kogod Center on Aging, and the National Institutes of Health (CA96985, J.M.v.D. and AG13925, J.L.K.).

Author information


  1. Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA

    • Darren J. Baker
    • , Tobias Wijshake
    • , Bennett G. Childs
    •  & Jan M. van Deursen
  2. Molecular Biology and Biochemistry, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA

    • Darren J. Baker
    •  & Jan M. van Deursen
  3. Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA

    • Darren J. Baker
    • , Tamar Tchkonia
    • , Nathan K. LeBrasseur
    • , James L. Kirkland
    •  & Jan M. van Deursen
  4. Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen University, Groningen 9700 RB, The Netherlands

    • Tobias Wijshake
    •  & Bart van de Sluis
  5. Physical Medicine and Rehabilitation, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA

    • Nathan K. LeBrasseur


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D.J.B., T.T., J.L.K., and J.M.v.D designed the INK-ATTAC strategy. D.J.B. and T.W. performed most of the experiments, T.T. did the rosiglitazone experiments, N.K.L. and B.G.C. assisted with the analysis of muscle functionality and in vitro senescence, respectively, and B.v.d.S. helped supervise T.W. The manuscript was written by D.J.B. and J.M.v.D. All authors discussed results, made figures and edited the manuscript. J.M.v.D. directed and supervised all aspects of the study.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jan M. van Deursen.

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