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_targeting cellular senescence prevents age-related bone loss in mice

Nature Medicine volume 23, pages 1072–1079 (2017)Cite this article

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A Corrigendum to this article was published on 01 November 2017

Abstract

Aging is associated with increased cellular senescence, which is hypothesized to drive the eventual development of multiple comorbidities1. Here we investigate a role for senescent cells in age-related bone loss through multiple approaches. In particular, we used either genetic (i.e., the INK-ATTAC 'suicide' transgene encoding an inducible caspase 8 expressed specifically in senescent cells2,3,4) or pharmacological (i.e., 'senolytic' compounds5,6) means to eliminate senescent cells. We also inhibited the production of the proinflammatory secretome of senescent cells using a JAK inhibitor (JAKi)3,7. In aged (20- to 22-month-old) mice with established bone loss, activation of the INK-ATTAC caspase 8 in senescent cells or treatment with senolytics or the JAKi for 2–4 months resulted in higher bone mass and strength and better bone microarchitecture than in vehicle-treated mice. The beneficial effects of _targeting senescent cells were due to lower bone resorption with either maintained (trabecular) or higher (cortical) bone formation as compared to vehicle-treated mice. In vitro studies demonstrated that senescent-cell conditioned medium impaired osteoblast mineralization and enhanced osteoclast-progenitor survival, leading to increased osteoclastogenesis. Collectively, these data establish a causal role for senescent cells in bone loss with aging, and demonstrate that _targeting these cells has both anti-resorptive and anabolic effects on bone. Given that eliminating senescent cells and/or inhibiting their proinflammatory secretome also improves cardiovascular function4, enhances insulin sensitivity3, and reduces frailty7, _targeting this fundamental mechanism to prevent age-related bone loss suggests a novel treatment strategy not only for osteoporosis, but also for multiple age-related comorbidities.

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Figure 1: Clearance of p16Ink4a+ senescent cells prevents age-related bone loss.
Figure 2: Senescent-cell clearance by treatment with senolytics (D + Q) prevents age-related bone loss.
Figure 3: The SASP increases osteoclastogenesis in vitro by promoting the survival of monocyte osteoclast progenitors.
Figure 4: Suppression of the SASP by treatment with the JAK1/2 inhibitor ruxolitinib prevents age-related bone loss.

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Acknowledgements

This work was supported by NIH grants P01 AG004875 (S.K.), R01 AG048792 (S.K.), K01 AR070241 (J.N.F.), K01 AR070281 (M.M.W.), R01 AR068275 (D.G.M.), R37 AG013925 (J.L.K.), AG R21 049182 (J.L.K.), the Connor Group, the Noaber, and the Ted Nash Foundations (J.L.K.), the Glenn Foundation (J.L.K., N.K.L.), and both a High-Risk Pilot Award (J.N.F. and S.K.) and Career Development Awards (J.N.F. and M.M.W.) from the Mayo Clinic Robert and Arlene Kogod Center on Aging, as well as the Richard F. Emslander Career Development Award in Endocrinology (J.N.F.), the James A. Ruppe Career Development Award in Endocrinology (M.M.W.), and the Glenn/American Federation for Aging Research Postdoctoral Fellowship for Translational Research on Aging (M.X.). We thank M. Ruan, G.L. Evans, B.S. Thicke, and J.M. Peterson (Mayo Clinic) for their technical assistance. We also thank A.R. Thoreson, A.W. Hooke (Mayo Clinic), and the Mayo Clinic Materials and Structural Testing Resource Laboratory for performing the bone biomechanical compression and nano-indentation testing.

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  1. Joshua N Farr, Ming Xu and Megan M Weivoda: These authors contributed equally to this work.

Authors and Affiliations

  1. Robert and Arlene Kogod Center on Aging and Division of Endocrinology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA

    Joshua N Farr, Ming Xu, Megan M Weivoda, David G Monroe, Daniel G Fraser, Jennifer L Onken, Brittany A Negley, Jad G Sfeir, Mikolaj B Ogrodnik, Christine M Hachfeld, Nathan K LeBrasseur, Matthew T Drake, Robert J Pignolo, Tamar Pirtskhalava, Tamara Tchkonia, Merry Jo Oursler, James L Kirkland & Sundeep Khosla

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Contributions

J.N.F. performed most of the experiments and analyses on INK-ATTAC and D + Q–treated mice. M.X. generated conditioned medium and defined the SASP mechanism. M.M.W. performed osteoclast cell culture experiments. M.X. and M.M.W. performed most of the experiments and analyses on JAKi-treated mice. D.G.M. provided technical guidance. D.G.F., J.L.O., B.A.N., J.G.S., M.B.O., C.M.H., T.P., T.T., N.K.L., M.T.D., R.J.P., and M.J.O. assisted with various aspects of the experiments and analyses. J.N.F., M.X., M.M.W., T.T., J.L.K., and S.K. contributed to the design of experiments. J.N.F., M.W., and S.K. wrote the manuscript with input from all co-authors. S.K. directed and supervised all aspects of the study in collaboration with J.L.K. All authors reviewed the manuscript.

Corresponding authors

Correspondence to James L Kirkland or Sundeep Khosla.

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Competing interests

J.L.K., T.T., and T.P. have a financial interest related to this research. A patent on senolytic drugs (WO2015116735A1) is held by 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.

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Farr, J., Xu, M., Weivoda, M. et al. _targeting cellular senescence prevents age-related bone loss in mice. Nat Med 23, 1072–1079 (2017). https://doi.org/10.1038/nm.4385

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