Targeting cellular senescence prevents age-related bone loss in mice

Joshua Farr, Ming Xu, Megan 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 M Drake, Robert Pignolo, Tamar Pirtskhalava, Tamara Tchkonia, Merry Jo Oursler, James L Kirkland, Sundeep Khosla

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Abstract

Aging is associated with increased cellular senescence, which is hypothesized to drive the eventual development of multiple comorbidities. 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 cells) or pharmacological (i.e., 'senolytic' compounds) means to eliminate senescent cells. We also inhibited the production of the proinflammatory secretome of senescent cells using a JAK inhibitor (JAKi). 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 function, enhances insulin sensitivity, and reduces frailty, 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.

Original languageEnglish (US)
Pages (from-to)1072-1079
Number of pages8
JournalNature Medicine
Volume23
Issue number9
DOIs
StatePublished - Sep 1 2017

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ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Farr, J., Xu, M., Weivoda, M., Monroe, D. G., Fraser, D. G., Onken, J. L., Negley, B. A., Sfeir, J. G., Ogrodnik, M. B., Hachfeld, C. M., LeBrasseur, N. K., Drake, M. M., Pignolo, R., Pirtskhalava, T., Tchkonia, T., Oursler, M. J., Kirkland, J. L., & Khosla, S. (2017). Targeting cellular senescence prevents age-related bone loss in mice. Nature Medicine, 23(9), 1072-1079. https://doi.org/10.1038/nm.4385