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

炎症性疾病限制健康寿命，其定义是一个人在健康状态下度过的生命长度。我们提出了一个 对最近一项由NIA资助的先期代谢健康和健康试验中已确定样本的辅助研究 二甲双胍(国歌)，将定义将受益于二甲双胍干预的健康人的特征 在慢性炎症等与年龄相关的健康风险出现之前。国歌质疑一个出乎意料的结果 二甲双胍和运动的双重干预：二甲双胍改善新陈代谢健康优于单独运动 超重/肥胖胰岛素抵抗受试者，但二甲双胍钝化运动介导的改善 其他类似胰岛素敏感受试者的代谢健康状况。国歌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影响的研究 招募总体健康的受试者，以解决增寿剂必须在以下时间之前开始的一般范式 出现与年龄相关的合并症以获得最大益处。拟议中的工作将增加一只发炎手臂 国歌。我们的辅助研究的主要终点将是细胞因子图谱，一种生物信息学的组合 细胞因子揭示了一种以前未被认识的Th17特征，这种特征会随着年龄的增长而自然发展。 这一特征类似于2型糖尿病患者的全身特征，因此提示两者之间存在机械性联系。 炎症和这一对健康的重大挑战。二甲双胍介导的线粒体修复 生物能量学与改进的非线粒体自噬相结合，降低了样本中的Th17谱 来自较老的受试者。相比之下，可以说，二甲双胍降低了年轻受试者细胞产生的IL-10 增加炎症。我们用独特的方法来定义“炎症”，从而阐明了 二甲双胍的作用，同时呼应上面总结的运动研究的概念：二甲双胍可能受益 受试者面临亚临床健康挑战，同时对更健康的人产生负面影响。我们会申请 通过分析已识别的国歌样本来询问二甲双胍对炎症的影响的类似方法 在自然胰岛素敏感性低的健康受试者中验证二甲双胍干预降低胰岛素敏感性的假设 已知的助长慢性炎症的细胞因子，通过改善线粒体生物能量学和增加非 免疫细胞中的线粒体自噬。第二种假设是二甲双胍将会有一个 对高度胰岛素敏感的受试者的免疫细胞有负面或无影响。机械的洞察力 将分析二甲双胍对免疫细胞的作用与身体成分、衰老生物标志物、 血糖控制，以及为国歌收集的骨骼肌结果。平行体外操作 免疫细胞中的线粒体功能和自噬将在 二甲双胍、细胞生理学和细胞因子谱。提议的项目取得成功，并配以国歌 结果将定义将受益于预防性二甲双胍的患者的特征，或许还会更多 重要的是，确定哪些人可能会受到积极使用二甲双胍的伤害。

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.