Long-term every-other-day administration of DMAMCL has little effect on aging and age-associated physiological decline in mice
Long-term every-other-day administration of DMAMCL has little effect on aging and age-associated physiological decline in mice
复制标题
长期每隔一天给予 DMAMCL 对小鼠衰老和与年龄相关的生理衰退影响不大
DOI：
10.18632/aging.101932
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发表时间：
2019-05-15
期刊：
影响因子：
5.2
通讯作者：
Chen, Jun
中科院分区：
文献类型：
--
作者：
Sun, Zhaomeng;Zhao, Lijun;Chen, Jun
转录因子NF-kappa B的激活目前被认为是衰老过程的驱动力之一。在动物模型中，核因子-kappaB信号通路的遗传损伤或核因子-kappaB活性的药物抑制可以延长动物模型的健康和寿命，并延缓或减轻许多与年龄相关的症状。然而，目前还缺乏基于合适的小分子化合物抑制核因子-kappaB的衰老干预策略。水溶性二甲氨基菊酯(DMAMCL)可以抑制核因子-kappaB的活性，目前正在进行临床试验。在这项研究中，我们发现，从1岁的雄性小鼠开始服用15个月的DMAMCL是耐受性和安全性很好的，并且对一些与年龄相关的症状，如神经行为表型、体能、心功能、血液学参数、免疫衰老表型、临床化学参数和血糖稳态都有改善或几乎没有影响。在分子水平上，DMAMCL可降低血清中几种与年龄相关的炎性细胞因子的水平，包括IL-6、IL-1α、IL-1β、肿瘤坏死因子-α、干扰素-γ和CXCL2，并抑制几种老年组织中的核因子-kappaB活性。综上所述，我们的结果表明，目前的DMAMCL给药策略可能对小鼠的衰老过程影响不大，并为进一步开发基于DMAMCL的衰老干预以促进健康衰老的可能性提供了基本线索。
The activation of transcription factor NF-kappa B is currently identified as one of the driving forces to the aging process. Genetic impairment of NF-kappa B signaling pathway or pharmacological inhibition of NF-kappa B activity has been shown to extend healthspan and lifespan in animal models, and delay or reduce many age-related symptoms. However, the aging intervention strategies based on NF-kappa B inhibition by the suitable small molecular compound is currently still lacking. The water-soluble dimethylaminomicheliolide (DMAMCL), can inhibit NF-kappa B activity and is currently undergoing clinical trials. In this study, we showed that 15 months of DMAMCL administration started in 1-year old male mice was well-tolerated and safe, and improved or had little effect on some age-associated symptoms, such as neurobehavioral phenotypes, physical performance, cardiac function, hematological parameters, immune aging phenotypes, clinical chemistry parameters, and glucose homeostasis. At the molecular level, DMAMCL administration mitigated serum levels of several age-associated inflammatory cytokines, including IL-6, IL-1 alpha, IL-1 beta, TNF-alpha, IFN-gamma, and CXCL2, and inhibited NF-kappa B activity in several aged tissues. Collectively, our results indicate that current strategy of DMAMCL administration may has little effect on aging process in mice, and provide basic clues to further exploit the possibility of DMAMCL-based aging intervention to promote healthy aging.