Targeting cellular senescence prevents age-related bone loss in mice

By J. Farr, Ming Xu, Megan M. Weivoda, D. Monroe, Daniel G. Fraser, Jennifer L Onken, Brittany A Negley, J. Sfeir, M. Ogrodnik, Christine M. Hachfeld and 8 more. Nature Medicine, 2017

1,011 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Immunology, Physiology

View Paper: https://www.semanticscholar.org/paper/981705f0befc92ed4927bfc23778e7f498594910

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In Cancer Research

1. Jesús Gil
2. J. Kirkland
3. T. Tchkonia

In Immunology

1. J. Kirkland
2. T. Tchkonia
3. Yi Zhu
4. Jesús Gil
5. M. Demaria

In Physiology

1. J. Kirkland
2. T. Tchkonia
3. Jesús Gil
4. M. Demaria
5. Nathan K. LeBrasseur
6. T. Pirtskhalava
7. Yi Zhu
8. S. Khosla

Citations in the corpus

• Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease (2019, background): “Consistent with the decreases in senescent cell burden and coupled decreases in adipose tissue macrophages from humans with diabetes and CKD reported here, we found that D+Q significantly decreases CLS in abdominal subcutaneous adipose tissue (p = 0·001).”
• Fisetin is a senotherapeutic that extends health and lifespan (2018, background): “Intermittent oral D + Q treatment improves pulmonary function and reduces pulmonary fibrosis in a bleomycin-induced murine model of idiopathic pulmonary fibrosis [35], reduces high fat diet-induced liver steatosis [36], alleviates gait impairment caused by leg irradiation [30] and reduces osteoporos”
• Aging and aging-related diseases: from molecular mechanisms to interventions and treatments (2022, background): “SASP factors in the supernatant of senescent cell culture can promote the survival of osteoclast progenitor cells and inhibit osteoblast differentiation.(370) MSCs located in the bone marrow and spongy bone are responsible for maintaining the balance of bone resorption and formation.”
• Senescence and the SASP: many therapeutic avenues (2020, background): “For instance, the JAK1/2 inhibitor ruxolitinib reduces the proinflammatory SASP, in vitro and in vivo and enhances insulin sensitivity, limits osteoporosis and reduces frailty in ageing mice (Xu et al. 2015a,b; Farr et al. 2017).”
• Cellular Senescence: Aging, Cancer, and Injury. (2019, background): “The transplantation of senescent ear cartilage fibroblasts into the knee joints of mice results in a gain of osteoarthritic symptoms, such as articular cartilage damage and osteocyte formation (116).”