| First Author | Farr JN | Year | 2017 |
| Journal | Nat Med | Volume | 23 |
| Issue | 9 | Pages | 1072-1079 |
| PubMed ID | 28825716 | Mgi Jnum | J:255294 |
| Mgi Id | MGI:6103967 | Doi | 10.1038/nm.4385 |
| Citation | Farr JN, et al. (2017) Targeting cellular senescence prevents age-related bone loss in mice. Nat Med 23(9):1072-1079 |
| abstractText | 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. |
