Sun Zhaomeng, Zhao Lijun, Su Li, Fang Qing, Xu Chenzhong, Su Yuanyuan, Liang Yao, Li Guodong, Xue Yanxue, Tong Tanjun, Chen Jun
Peking University Research Center on Aging, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Department of Integration of Chinese and Western Medicine, School of Basic Medical Science, Peking University, Beijing 100191, China.
Center of Medical and Health Analysis, Peking University, Beijing, China.
Aging (Albany NY). 2019 May 2;11(9):2583-2609. doi: 10.18632/aging.101932.
The activation of transcription factor NF-κB is currently identified as one of the driving forces to the aging process. Genetic impairment of NF-κB signaling pathway or pharmacological inhibition of NF-κB 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-κB inhibition by the suitable small molecular compound is currently still lacking. The water-soluble dimethylaminomicheliolide (DMAMCL), can inhibit NF-κB 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-1α, IL-1β, TNF-α, IFN-γ, and CXCL2, and inhibited NF-κB 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.
转录因子NF-κB的激活目前被认为是衰老过程的驱动因素之一。在动物模型中，NF-κB信号通路的基因损伤或NF-κB活性的药理学抑制已被证明可延长健康寿命和寿命，并延迟或减轻许多与年龄相关的症状。然而，目前仍然缺乏基于合适的小分子化合物抑制NF-κB的衰老干预策略。水溶性二甲基氨基米氏内酯（DMAMCL）可抑制NF-κB活性，目前正在进行临床试验。在本研究中，我们发现，对1岁雄性小鼠开始给予15个月的DMAMCL，耐受性良好且安全，对一些与年龄相关的症状，如神经行为表型、身体性能、心脏功能、血液学参数、免疫衰老表型、临床化学参数和葡萄糖稳态，有改善作用或影响不大。在分子水平上，给予DMAMCL可降低几种与年龄相关的炎性细胞因子的血清水平，包括IL-6、IL-1α、IL-1β、TNF-α、IFN-γ和CXCL2，并抑制多个衰老组织中的NF-κB活性。总体而言，我们的结果表明，目前给予DMAMCL的策略可能对小鼠的衰老过程影响不大，并为进一步探索基于DMAMCL的衰老干预以促进健康衰老的可能性提供了基本线索。
