AbstractChronic high-altitude hypoxia (CHH) induces irreversible abnormalities in various organisms. Emerging evidence indicates that CHH markedly suppresses bone mass and bone strength. Targeting senescent cells and the consequent senescence-associated secretory phenotype (SASP) with senolytics is a recently developed novel therapy for multiple age-related diseases.

摘要慢性高原缺氧（CHH）在各种生物体中引起不可逆的异常。新出现的证据表明，CHH显着抑制骨量和骨强度。针对衰老细胞和随之而来的衰老相关分泌表型（SASP）与senolytics是最近开发的一种针对多种年龄相关疾病的新型疗法。

The combination of dasatinib and quercetin (DQ) has been proven to selectively target senescent cells and attenuate SASP in multiple tissues. In this study, experimental mice were subjected to an environment simulating 5,000 m above sea level for 8 weeks to induce CHH conditions. Our results indicated that DQ supplementation was well-tolerated with negligible toxicity.

达沙替尼和槲皮素（DQ）的组合已被证明可选择性靶向衰老细胞并减弱多种组织中的SASP。在这项研究中，将实验小鼠置于模拟海拔5000米的环境中8周，以诱导CHH条件。我们的结果表明，DQ补充剂耐受性良好，毒性可忽略不计。

In vivo, DQ prevented reductions in BMD and BMC and improved bone microarchitecture against CHH-induced changes. Biomechanical testing demonstrated that DQ significantly improved the mechanical properties of femoral bones in CHH-exposed mice. Furthermore, DQ mitigated senescence in LepR + BMSCs and decreased the population of senescent cells, as evidenced by reduced senescence markers and SA-β-Gal staining.

在体内，DQ阻止了BMD和BMC的减少，并改善了针对CHH诱导的变化的骨微结构。生物力学测试表明，DQ显着改善了CHH暴露小鼠股骨的力学性能。此外，DQ减轻了LepR+ BMSCs的衰老，并减少了衰老细胞的数量，衰老标志物减少和SA-β-Gal染色证明了这一点。

An analysis of serum and bone marrow aspirates showed that DQ treatment preserved angiogenic and osteogenic coupling in the bone marrow microenvironment by maintaining type H vessels and angiogenic growth factors. The results suggest that DQ has significant anti-senescence effects on BMSCs and a positive impact on the bone marrow microenvironment, supporting its clinical investigation as a therapeutic agent for CHH-related osteoporosis..

对血清和骨髓抽吸物的分析表明，DQ治疗通过维持H型血管和血管生成生长因子来维持骨髓微环境中的血管生成和成骨偶联。结果表明，DQ对BMSCs具有显着的抗衰老作用，并对骨髓微环境产生积极影响，支持其作为CHH相关性骨质疏松症治疗剂的临床研究。。

IntroductionSudden exposure to high altitudes is well-documented to induce acute mountain sickness, primarily driven by the decreased atmospheric partial pressure of oxygen and resulting in tissue hypoxia1,2,3. Moreover, chronic exposure to such hypoxia contributes to irreversible abnormalities across several systems like respiratory, cardiovascular, haematological, and neurological4,5.

引言有充分证据表明，突然暴露于高海拔地区会诱发急性高原病，主要是由于大气氧分压降低导致组织缺氧1,2,3。此外，长期暴露于这种缺氧会导致呼吸，心血管，血液学和神经学等几个系统的不可逆异常4,5。

Among these, the impact on bone health, specifically bone deterioration due to high-altitude exposure, has increasingly commanded attention6. Evidence from recent studies suggests a notable decrease in bone mass and mechanical strength in rodents subjected to both acute and chronic high-altitude conditions, alongside aberrations in skeletal metabolism marked by escalated bone resorption and diminished bone formation activities7,8,9,10,11.

其中，对骨骼健康的影响，特别是由于高海拔暴露导致的骨骼恶化，越来越受到关注6。最近研究的证据表明，在急性和慢性高海拔条件下，啮齿动物的骨量和机械强度显着下降，骨骼代谢异常以骨吸收增加和骨形成活动减少为特征7,8,9,10,11。

Similarly, clinical studies have corroborated these findings in humans, revealing significant reductions in bone mineral density and bone-forming activity at high to extreme altitudes, with a challenging full recovery post-return to sea level6,12,13. Despite growing interest, the quest for effective and safe interventions against high-altitude-induced bone deterioration remains largely unfulfilled, underscoring an urgent need for novel therapeutic paradigms.The phenomenon of cellular senescence denotes an inevitable fate for aging cells, characterized by an irreversible halt in proliferation, potent mitogenic signals, telomere shortening, DNA damage, and increased reactive oxygen species (ROS) production14,15.

同样，临床研究证实了人类的这些发现，揭示了在高海拔到极端海拔地区骨矿物质密度和骨形成活性的显着降低，并且在返回海平面后具有挑战性的完全恢复6,12,13。尽管人们越来越感兴趣，但对高海拔引起的骨骼恶化的有效和安全干预措施的追求在很大程度上仍未实现，这强调了迫切需要新的治疗范例。细胞衰老现象意味着衰老细胞不可避免的命运，其特征是增殖不可逆停止，有效的促有丝分裂信号，端粒缩短，DNA损伤和活性氧（ROS）产生增加14,15。

Senescent cells exhibit a senescence-associated secretory phenotype (SASP), inherently pro-inflammatory and contributing to various diseases14. Notably, the role of cellular senescence in osteoporosis16, previously underrecognized, has emerged as .

衰老细胞表现出衰老相关的分泌表型（SASP），固有地促炎并导致各种疾病14。值得注意的是，先前未被认识到的细胞衰老在骨质疏松症中的作用16已经出现。

Data availability

数据可用性

The data during the current study are available from the corresponding author, Q.G., upon reasonable request.

本研究期间的数据可根据合理要求从通讯作者Q.G.处获得。

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Download referencesAcknowledgementsThis study was supported by the Postdoctoral Research Foundation of China (Grant No. 2020M681739), the Research Funding Project of the Jiangsu Commission of Health (Grant No. Z2021046, LKM2022048), the Research Funding Project of Xuzhou Medical University (Grant No.

下载参考文献致谢本研究得到了中国博士后研究基金（批准号2020M681739），江苏省卫生委员会研究资助项目（批准号Z2021046，LKM2022048），徐州医科大学研究资助项目（批准号：。

XZSYSKF2020004), the Xuzhou Institute of Technology (Grant No. KC22273), Health Commission of Changzhou City (Grant No. ZD202340), and Research project of Qinghai Provincial Health Commission (Grant No.2023-wjzdx-106).Author informationAuthor notesShen Wang and Juan Zhai equally to this work.Authors and AffiliationsCentral Lab, Pizhou Hospital, Xuzhou Medical University, Xuzhou, 221300, ChinaShen Wang, Juan Zhai, Xingchen Song, Huaiyuan Zhai, Chengbai Dai, Jian Li, Fei Teng, Junli Huang, Guoqiang Wang, Rui Geng, Qingguo Lu, Xinfa Nie, Kui Xue, Qilong Wang, Wanying Huang, Huanyu Zhang, Dehong Yu, Yanhong Liu, Yilong Guo & Qinghe GengKey Laboratory of Clinical Research of Osteoporosis, Xuzhou Medical University, Xuzhou, 221300, ChinaShen Wang, Juan Zhai, Xingchen Song, Huaiyuan Zhai, Chengbai Dai, Jian Li, Fei Teng, Junli Huang, Guoqiang Wang, Rui Geng, Qingguo Lu, Xinfa Nie, Kui Xue, Qilong Wang, Wanying Huang, Huanyu Zhang, Dehong Yu, Yanhong Liu, Yilong Guo & Qinghe GengKey Laboratory of Trauma and Neural Regeneration, Ministry of Education, Beijing, 100044, ChinaShen WangTrauma Medicine Center, Peking University People’s Hospital, Beijing, 100044, ChinaShen WangDepartment of Orthopedics, Changzhou Second Hospital, Nanjing Medical University, Changzhou, 213000, ChinaKe HengDepartment of Traditional Chinese Medicine, Pizhou Hospital of Traditional Chinese Medicine, Xuzhou, 221300, ChinaLiangwei ShaXuzhou Vocational College of Bioengineering, Xuzhou, 22130.

XZSYSKF2020004），徐州理工学院（批准号KC22273），常州市卫生委员会（批准号ZD202340）和青海省卫生委员会研究项目（批准号2023-wjzdx-106）。作者信息作者注意到王慎和翟娟同样支持这项工作。作者和所属单位徐州医科大学邳州医院中心实验室，徐州，221300，王慎，翟娟，宋兴晨，翟怀远，戴成白，李健，滕飞，黄俊丽，王国强，耿睿，卢庆国，聂新发，薛奎，王启龙，黄万英，张焕宇，余德宏，刘艳红，郭怡龙和清河耿基骨质疏松症临床研究实验室，徐州医科大学，徐州，221300，王慎，翟娟，宋兴辰，翟怀远，戴成白，李健，滕飞，黄俊丽，王国强，耿睿，卢庆国，聂新发，薛奎，王奇龙，黄万英，张环宇，余德宏，刘艳红，郭怡龙和庆河耿基教育部创伤与神经再生实验室，北京，100044，北京大学人民医院王国申创伤医学中心，北京，100044，王国深南京医科大学常州第二医院骨科，常州213000，徐州邳州中医院中医科，221300，徐州生物工程职业学院，22130。

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PubMed Google ScholarContributionsQ.G. and Y.G. wrote the manuscript; Y.G. revised the manuscript; Y.G. conceived and designed the study; Q.G., S.W., J.Z., K.H., L.S., X.S., C.D., H.Z., J.L., F.T., J.H., G.W., Y.G., R.G., Q.L., X.N., K.X., Q.W., W.H., H.Z., Y.Y., J.L., D.Y., and Y.L performed the study and collected the data; Q.G.

PubMed谷歌学术贡献。G、 和Y.G.写了手稿；Y、 G.修改了手稿；Y、 G.构思和设计了这项研究；Q、 G.，S.W.，J.Z.，K.H.，L.S.，X.S.，C.D.，H.Z.，J.L.，F.T.，J.H.，G.W.，Y.G.，R.G.，Q.L.，X.N.，K.X.，Q.W.，W.H.，H.Z.，Y.Y.，J.L.，D.Y。和Y.L进行了研究并收集了数据；Q、 G。

and Y.G. analyzed the data. All authors reviewed the manuscript.Corresponding authorsCorrespondence to.

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Reprints and permissionsAbout this articleCite this articleWang, S., Zhai, J., Heng, K. et al. Senolytic cocktail dasatinib and quercetin attenuates chronic high altitude hypoxia associated bone loss in mice.

转载和许可本文引用本文Wang，S.，Zhai，J.，Heng，K。等人。Senolytic鸡尾酒达沙替尼和槲皮素可减轻小鼠慢性高原缺氧相关的骨质流失。

Sci Rep 14, 30417 (2024). https://doi.org/10.1038/s41598-024-82262-5Download citationReceived: 09 July 2024Accepted: 03 December 2024Published: 06 December 2024DOI: https://doi.org/10.1038/s41598-024-82262-5Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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KeywordsOsteoporosisChronic hypobaric hypoxia (CHH)Dasatinib and quercetin (DQ)Bone marrow stem cells (BMSCs)AngiogenesisCellular senescenceSenescence-associated secretory phenotype (SASP)

关键词骨质疏松症低压缺氧（CHH）达沙替尼和槲皮素（DQ）骨髓干细胞（BMSCs）血管生成细胞衰老相关分泌表型（SASP）