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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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.
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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