Letter | Published:

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

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

Abstract

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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References

  1. 1.

    Cellular senescence: putting the paradoxes in perspective. Curr. Opin. Genet. Dev. 21, 107–112 (2011)

  2. 2.

    , , & The essence of senescence. Genes Dev. 24, 2463–2479 (2010)

  3. 3.

    Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120, 513–522 (2005)

  4. 4.

    et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 6, e301 (2008)

  5. 5.

    & Four faces of cellular senescence. J. Cell Biol. 192, 547–556 (2011)

  6. 6.

    et al. Fat apoptosis through targeted activation of caspase 8: a new mouse model of inducible and reversible lipoatrophy. Nature Med. 11, 797–803 (2005)

  7. 7.

    & The regulation of INK4/ARF in cancer and aging. Cell 127, 265–275 (2006)

  8. 8.

    et al. Ink4a/Arf expression is a biomarker of aging. J. Clin. Invest. 114, 1299–1307 (2004)

  9. 9.

    , , & Characterization of regulatory elements on the promoter region of p16INK4a that contribute to overexpression of p16 in senescent fibroblasts. J. Biol. Chem. 276, 48655–48661 (2001)

  10. 10.

    et al. BubR1 N terminus acts as a soluble inhibitor of cyclin B degradation by APC/CCdc20 in interphase. Dev. Cell 16, 118–131 (2009)

  11. 11.

    , & Unattached kinetochores catalyze production of an anaphase inhibitor that requires a Mad2 template to prime Cdc20 for BubR1 binding. Dev. Cell 16, 105–117 (2009)

  12. 12.

    et al. BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice. Nature Genet. 36, 744–749 (2004)

  13. 13.

    , , & Mutant mice with small amounts of BubR1 display accelerated age-related gliosis. Neurobiol. Aging 28, 921–927 (2007)

  14. 14.

    et al. Aging-associated vascular phenotype in mutant mice with low levels of BubR1. Stroke 38, 1050–1056 (2007)

  15. 15.

    et al. Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency. Nature Cell Biol. 10, 825–836 (2008)

  16. 16.

    et al. PPARγ accelerates cellular senescence by inducing p16INK4α expression in human diploid fibroblasts. J. Cell Sci. 121, 2235–2245 (2008)

  17. 17.

    , , , & Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593–602 (1997)

  18. 18.

    et al. Expression profiles of p53-, p16INK4a-, and telomere-regulating genes in replicative senescent primary human, mouse, and chicken fibroblast cells. Exp. Cell Res. 272, 199–208 (2002)

  19. 19.

    & Epigenetic regulation of the INK4bARFINK4a locus: in sickness and in health. Epigenetics 5, 685–690 (2010)

  20. 20.

    & Regulation of the INK4bARFINK4a tumour suppressor locus: all for one or one for all. Nature Rev. Mol. Cell Biol. 7, 667–677 (2006)

  21. 21.

    et al. Expression of linear and novel circular forms of an INK4/ARF-associated non-coding RNA correlates with atherosclerosis risk. PLoS Genet. 6, e1001233 (2010)

  22. 22.

    , & Regulatory mechanisms of tumor suppressor P16INK4A and their relevance to cancer. Biochemistry 50, 5566–5582 (2011)

  23. 23.

    et al. Senescence of activated stellate cells limits liver fibrosis. Cell 134, 657–667 (2008)

  24. 24.

    & The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing. Nature Cell Biol. 12, 676–685 (2010)

  25. 25.

    & A protocol for isolation and culture of mesenchymal stem cells from mouse bone marrow. Nature Protocols 4, 102–106 (2009)

  26. 26.

    et al. Cdc20 hypomorphic mice fail to counteract de novo synthesis of cyclin B1 in mitosis. J. Cell Biol. 191, 313–329 (2010)

  27. 27.

    et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl Acad. Sci. USA 92, 9363–9367 (1995)

  28. 28.

    , & Effects of fat depot site on differentiation-dependent gene expression in rat preadipocytes. Int. J. Obes. Relat. Metab. Disord. 20 (Suppl 3). S102–S107 (1996)

  29. 29.

    et al. Myostatin inhibition enhances the effects of exercise on performance and metabolic outcomes in aged mice. J. Gerontol. A Biol. Sci. Med. Sci. 64A, 940–948 (2009)

  30. 30.

    et al. iPS programmed without c-MYC yield proficient cardiogenesis for functional heart chimerism. Circ. Res. 105, 648–656 (2009)

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Acknowledgements

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

Affiliations

  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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Contributions

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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DOI

https://doi.org/10.1038/nature10600

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