The impact of insulin sensitivity on the potential of metformin to delay age-related inflammation

炎症性疾病限制了健康寿命，健康寿命的定义是一个人在健康状态下度过的时间。我们提出了一个 对最近由NIA资助的一项试验中的去识别样本进行的辅助研究， 二甲双胍（ANTHEM）将定义从二甲双胍干预中获益的健康人群的特征 在慢性炎症等与年龄相关的健康风险发生之前。ANTHEM查询的意外结果 二甲双胍和运动的双重干预：二甲双胍改善代谢健康优于单独运动， 超重/肥胖胰岛素抵抗受试者，但二甲双胍减弱了运动介导的改善， 在其他方面类似的胰岛素敏感受试者的代谢健康。ANTHEM测试基线代谢的影响 二甲双胍单药治疗对胰岛素敏感性和骨骼肌线粒体的影响 招募总体健康的受试者，以解决寿命增强剂必须在 年龄相关合并症的发生，以获得最大获益。拟议的工作将增加一个炎症手臂， ANTHEM。我们的辅助研究的主要终点是细胞因子谱，这是一种生物信息学组合， 这些细胞因子揭示了以前未被重视的Th 17特征，其随着年龄的增长而自然地全身性发展。 这一特征与2型糖尿病的全身特征相似，因此表明糖尿病与糖尿病之间存在机制联系。 炎症和这一对健康的重大挑战。二甲双胍介导的线粒体损伤修复 生物能量学与改善的非线粒体自噬相结合，降低了样品中的Th 17特征 老的科目。相比之下，二甲双胍降低了年轻受试者细胞产生IL-10的能力， 增加炎症。我们定义“炎症”的独特方法因此阐明了 二甲双胍的作用，同时呼应了上述运动研究的概念：二甲双胍可能有益于 具有亚临床健康挑战的受试者，同时对更健康的人具有负面影响。我们将应用 通过分析去识别ANTHEM样本来查询二甲双胍对炎症的影响的类似方法， 检验二甲双胍干预天然低胰岛素敏感性健康受试者降低胰岛素敏感性的假设 细胞因子已知通过改善线粒体生物能学和增加非细胞因子来刺激慢性炎症， 免疫细胞中的线粒体自噬。次要假设是二甲双胍将具有 对来自高度胰岛素敏感受试者的免疫细胞有负面影响或没有影响。机械的见解， 二甲双胍对免疫细胞的作用将相对于身体组成，衰老生物标志物， ANTHEM的血糖控制和骨骼肌结果。平行离体操作 免疫细胞中的线粒体功能和自噬将在免疫细胞之间建立因果关系。 二甲双胍、细胞生理学和细胞因子谱。成功与拟议的项目加上ANTHEM 结果将定义从预防性二甲双胍中获益的人群的特征， 重要的是，识别那些可能因积极使用二甲双胍而受到伤害的人。

Inflammatory diseases limit healthspan, defined as the length of one's life spent in good health. We propose an ancillary study on deidentified samples from a recent NIA-funded trial Antecedent Metabolic Health and Metformin (ANTHEM) that will define traits of healthy people who would benefit from metformin intervention before onset of age-related health risks like chronic inflammation. ANTHEM queries an unexpected outcome of dual interventions of metformin and exercise: metformin improved metabolic health over exercise alone in overweight/obese insulin resistant subjects, but metformin blunted exercise-mediated improvements in metabolic health of otherwise similar insulin sensitive subjects. ANTHEM tests the impact of baseline metabolic health on the effects of metformin monotherapy on insulin sensitivity and skeletal muscle mitochondria by recruiting overall healthy subjects to address the general paradigm that lifespan enhancers must start prior to onset of age-related co-morbidities for maximal benefit. The proposed work will add an inflammation arm to ANTHEM. The primary endpoint of our ancillary study will be cytokine profiles, a bioinformatic combination of cytokines that revealed a previously unappreciated Th17 profile that naturally develops systemically with age. This profile is similar to the systemic profile in type 2 diabetes, and thus suggests a mechanistic link between inflammation and this major challenge to healthspan. Metformin-mediated repair of mitochondrial bioenergetics, in combination with improved non-mitochondrial autophagy, lowered the Th17 profile in samples from older subjects. In contrast, metformin lowered IL-10 production by cells from younger subjects, arguably increasing inflammation. Our unique approach to defining “inflammation” thus clarified mechanisms of metformin action, while echoing concepts from the exercise study summarized above: metformin may benefit subjects with sub-clinical health challenges while having a negative effect on healthier people. We will apply similar approaches to query metformin's effect on inflammation by analyzing deidentified ANTHEM samples to test the hypothesis that metformin intervention in healthy subjects with naturally low insulin sensitivity reduces cytokines known to fuel chronic inflammation, by improving mitochondrial bioenergetics and increasing non- mitochondrial autophagy in immune cells. The secondary hypothesis is that metformin will have either a negative or no impact on immune cells from highly insulin sensitive subjects. Mechanistic insights into metformin action on immune cells will be analyzed relative to changes in body composition, aging biomarkers, glycemic control, and skeletal muscle outcomes collected for ANTHEM. Parallel ex vivo manipulation of mitochondrial function and autophagy in immune cells will establish cause/effect relationships amongst metformin, cell physiology, and cytokine profiles. Success with the proposed project coupled with ANTHEM outcomes will define traits of people who would benefit from preventative metformin, and perhaps more importantly, to identify those who may be harmed by proactive metformin use.