Targeting cellular senescence prevents age-related bone loss in mice

JN Farr, M Xu, MM Weivoda, DG Monroe, DG Fraser… - Nature medicine, 2017 - nature.com
JN Farr, M Xu, MM Weivoda, DG Monroe, DG Fraser, JL Onken, BA Negley, JG Sfeir
Nature medicine, 2017nature.com
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 (ie, the INK-ATTAC'suicide'transgene encoding an inducible caspase 8 expressed
specifically in senescent cells,,) or pharmacological (ie,'senolytic'compounds,) means to
eliminate senescent cells. We also inhibited the production of the proinflammatory …
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.
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