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.

年龄是导致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。细胞因子分析和生物信息学分析表明，Th17 细胞因子产生区分 CD4 ⁺来自瘦、血糖正常的老年和年轻受试者的 T 细胞，并模拟与糖尿病相关的 Th17 谱。与年轻受试者相比，年龄较大的 T 细胞也存在与氧化还原失衡相关的自噬和线粒体生物能量学缺陷。二甲双胍通过增加自噬和改善线粒体生物能量来改善 Th17 炎症谱。相比之下，靶向自噬的 siRNA 破坏了年轻受试者 T 细胞中的氧化还原平衡，并通过激活 Th17 主调节因子 STAT3 来激活 Th17 谱，STAT3 反过来结合 IL-17A 和 F 启动子。靶向线粒体自噬的 siRNA 未能激活 Th17 谱。我们得出结论，二甲双胍在很大程度上同时改善了自噬和线粒体功能，以改善与糖尿病炎症相呼应的新定义的炎症特征。