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Abstract

Cellular senescence, a stress-induced irreversible growth arrest often characterized by expression of p16Ink4a (encoded by the Ink4a/Arf locus, also known as Cdkn2a) and a distinctive secretory phenotype, prevents the proliferation of preneoplastic cells and has beneficial roles in tissue remodelling during embryogenesis and wound healing. Senescent cells accumulate in various tissues and organs over time, and have been speculated to have a role in ageing. To explore the physiological relevance and consequences of naturally occurring senescent cells, here we use a previously established transgene, INK-ATTAC, to induce apoptosis in p16Ink4a-expressing cells of wild-type mice by injection of AP20187 twice a week starting at one year of age. We show that compared to vehicle alone, AP20187 treatment extended median lifespan in both male and female mice of two distinct genetic backgrounds. The clearance of p16Ink4a-positive cells delayed tumorigenesis and attenuated age-related deterioration of several organs without apparent side effects, including kidney, heart and fat, where clearance preserved the functionality of glomeruli, cardio-protective KATP channels and adipocytes, respectively. Thus, p16Ink4a-positive cells that accumulate during adulthood negatively influence lifespan and promote age-dependent changes in several organs, and their therapeutic removal may be an attractive approach to extend healthy lifespan.

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Acknowledgements

We thank M. Hamada, J. Rainey, Q. Guo, S. Bornschlegl, M. Li, C. M. Roos, N. Hamada and B. Zhang for assistance, and C. Burd, S. Reyes Ramirez, P. Galardy and D. Katzmann and the members of Program Project Grant AG041122 for discussions. We are grateful to R. Miller and S. Austad for help with the design and interpretation of our lifespan studies. We thank C. Burd and J. Campisi for sharing p16-FLUC and 3MR MEFs, respectively. This work was supported by the National Institutes of Health (J.M.v.D. R01CA96985 and AG041122 project 1) and (J.D.M., HL111121), the Paul F. Glenn Foundation (J.M.v.D. and D.J.B.), the Ellison Medical Foundation (D.J.B.), the Noaber Foundation (J.M.v.D.), the Children’s Research Center (D.J.B.) and the Robert and Arlene Kogod Center on Aging (D.J.B.).

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Affiliations

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

    • Darren J. Baker
    • , Matej Durik
    • , Melinde E. Wijers
    • , Jian Zhong
    • , Rachel A. Saltness
    • , Karthik B. Jeganathan
    •  & Jan M. van Deursen
  2. Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA

    • Bennett G. Childs
    • , Cynthia J. Sieben
    •  & Jan M. van Deursen
  3. Division of Cardiovascular Surgery, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA

    • Grace Casaclang Verzosa
    •  & Jordan D. Miller
  4. Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA

    • Abdulmohammad Pezeshki
    •  & Khashayarsha Khazaie

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Contributions

D.J.B. performed all lifespan and most healthspan analyses on ATTAC mice. B.G.C. designed and conducted experiments to identify and quantify X-gal-positive cells by TEM, and analysed mice for cardiomyocyte hypertrophy and local RAAS activity in kidney. M.E.W., J.Z. and R.A.S. assisted with various aspects of healthspan analyses: the extent of their contributions is reflected in the authorship order. C.J.S. conducted the lifespan analysis of C57BL/6-129Sv/E hybrid mice on diets containing 5% or 9% fat. K.B.J. investigated somatotrophic axis signaling. G.C.C.V., J.D.M. and M.D. analysed resting heart functions by echocardiography. M.D. designed and conducted cardiac stress tests. A.P. and K.K. analysed leukocyte subpopulations. J.M.v.D., D.J.B. and B.G.C. wrote the paper with input from all co-authors. J.M.v.D. directed and supervised all aspects of the study in collaboration with D.J.B.

Competing interests

J.M.v.D. and D.J.B. are inventors on patents licensed to Unity Biotechnology by Mayo Clinic and J.M.v.D. is a co-founder of Unity Biotechnology.

Corresponding authors

Correspondence to Darren J. Baker or Jan M. van Deursen.

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https://doi.org/10.1038/nature16932

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