Metformin Enhances Autophagy and Normalizes Mitochondrial Function to Alleviate Aging-Associated Inflammation
Metformin Enhances Autophagy and Normalizes Mitochondrial Function to Alleviate Aging-Associated Inflammation
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DOI：
10.1016/j.cmet.2020.04.015
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发表时间：
2020-07-07
期刊：
影响因子：
29
通讯作者：
Nikolajczyk, Barbara S.
中科院分区：
文献类型：
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作者：
Bharath, Leena P.;Agrawal, Madhur;Nikolajczyk, Barbara S.
年龄是与年龄相关疾病的炎症的不可改变的风险因素;因此，抗炎药物有望增加健康寿命。细胞因子谱和生物信息学分析表明，Th 17细胞因子的产生将CD 4（+）T细胞与瘦的、血糖正常的老年和年轻受试者区分开来，并模拟糖尿病相关的Th 17谱。与年轻受试者相比，老年受试者的T细胞在自噬和线粒体生物能量学方面也存在缺陷，这些缺陷与氧化还原失衡有关。美托洛尔通过增加自噬和改善线粒体生物能量学来改善Th 17炎症特征。相比之下，自噬靶向siRNA破坏了年轻受试者T细胞的氧化还原平衡，并通过激活Th 17主调节因子STAT 3激活了Th 17特征，STAT 3反过来又结合了IL-17 A和F启动子。线粒体自噬靶向siRNA未能激活Th 17特征。我们的结论是，二甲双胍改善自噬和线粒体功能在很大程度上是平行的，以改善一个新定义的炎症反应，反映糖尿病炎症。
Age is a non-modifiable risk factor for the inflammation that underlies age-associated diseases; thus, anti-inflammaging drugs hold promise for increasing health span. Cytokine profiling and bioinformatic analyses showed that Th17 cytokine production differentiates CD4(+) T cells from lean, normoglycemic older and younger subjects, and mimics a diabetes-associated Th17 profile. T cells from older compared to younger subjects also had defects in autophagy and mitochondrial bioenergetics that associate with redox imbalance. Metformin ameliorated the Th17 inflammaging profile by increasing autophagy and improving mitochondrial bioenergetics. By contrast, autophagy-targeting siRNA disrupted redox balance in T cells from young subjects and activated the Th17 profile by activating the Th17 master regulator, STAT3, which in turn bound IL-17A and F promoters. Mitophagy-targeting siRNA failed to activate the Th17 profile. We conclude that metformin improves autophagy and mitochondrial function largely in parallel to ameliorate a newly defined inflammaging profile that echoes inflammation in diabetes.