Mitochondrial Aging Promotes Inflammation

摘要： 线粒体老化促进炎症 老龄化通常与健康的进行性下降有关，从而导致生活质量下降，从而限制 健康跨度，定义为健康度过的年数。衰老研究的一个关键目标是增加 “健康跨度”。这一目标尤其重要，因为根据CDC的数据，65岁的美国成年人数量 到2030年，年龄将增加一倍以上，达到约7100万人，并提出健康跨度数据项目 除了明显的个人负担外，这是对我们医疗体系的一种难以为继的消耗。在众多的细胞中 随着年龄的增长而下降的过程，线粒体功能障碍尤其重要，因为许多研究 表明线粒体衰竭与年龄相关疾病的发展之间的联系。这项建议 该项目将评估年龄相关的线粒体易位STAT3(MitoSTAT3)作为一种 衰老的CD4T细胞对氧化磷酸化(OXPHOS)的异常依赖和受损 上调有氧糖酵解以促进炎症。我们的数据显示，来自瘦身的CD4T细胞 血糖正常的老年人(平均年龄62岁)产生更高数量的促炎Th17细胞因子 与瘦削的血糖正常的年轻人(平均年龄32岁)的细胞相比。我们通过实验证明了 这种促炎状态继发于线粒体呼吸异常、低糖酵解和 自噬功能受损，细胞循环过程会随着年龄的增长而下降。我们观察到T细胞 老年受试者有较高的mitoSTAT3，这已知在许多细胞类型中驱动对OXPHOS的依赖。我们 还观察到STAT3的线粒体易位是以自噬依赖的方式发生的。遗传 抑制年轻受试者T细胞的自噬，促进STAT3的线粒体易位， 导致生物能量和炎症的轮廓，模仿老化的T细胞。假设：预防 衰老诱导的STAT3线粒体移位可改善T细胞功能，减轻炎症。我们 将利用新开发的mitoSTAT3小分子抑制剂直接抑制线粒体 STAT3的易位或通过促进自噬而间接地限制mitoSTAT3。我们假设 限制mitoSTAT3促进的代谢重编程将导致更高的糖酵解和更低的糖酵解 OXPHOS依赖，改善T细胞功能，减轻炎症。我们将建立事业和 通过使用遗传学和药理学功能得失的方法来操纵mitoSTAT3的效果。这 机制工作将绘制出mitoSTAT3在调节T细胞代谢和炎症过程中的作用 衰老，并对改善健康寿命的目标具有治疗意义。 。

Abstract: Mitochondrial Aging Promotes Inflammation Aging is often associated with a progressive decline in health resulting in a decline in the quality of life that limits healthspan, defined as number of years spent in good health. One critical goal of aging research is to increase “healthspan”. This goal is especially important because according to CDC, the number of US adults aged >65 or older will more than double to approximately 71 million by the year 2030, and present healthspan data project an untenable drain on our healthcare system in addition to the obvious personal burden. Of the many cellular processes that decline with age, mitochondrial dysfunction is especially important because numerous studies show a link between failing mitochondria and the development of age-associated diseases. This proposed project will evaluate age associated mitochondrial translocation of STAT3(mitoSTAT3) as the driver of an aberrant addictive dependence of aging CD4+ T cells on oxidative phosphorylation(oxphos) and impaired upregulation of the aerobic glycolysis to promote inflammation. Our data shows that CD4+ T cells from lean normoglycemic older adults (avg age 62 yrs) produce higher amounts of proinflammatory Th17 cytokines compared to cells from lean normoglycemic younger adults (avg age 32 yrs). We experimentally established that this proinflammatory profile was secondary to an aberrant mitochondrial respiratory profile, lower glycolysis and impairment in autophagy, the cellular recycling process known to decline with age. We observed that T cells from older subjects had higher mitoSTAT3, which is known to drive oxphos dependence in many cell types. We also observed that mitochondrial translocation of STAT3 occurred in an autophagy dependent manner. Genetic inhibition of autophagy in T cells from younger subjects, promoted mitochondrial translocation of STAT3, resulting in a bioenergetic and inflammatory profile that mimicked that of aging T cells. Hypothesis: Preventing aging induced mitochondrial translocation of STAT3 improves T cell function and alleviates inflammation. We will utilize the newly developed small molecule inhibitors of mitoSTAT3 to either directly inhibit mitochondrial translocation of STAT3 or indirectly by promoting autophagy and thereby limit mitoSTAT3. We hypothesize that the metabolic reprogramming promoted by limiting mitoSTAT3, would result in higher glycolysis and lower oxphos dependence, improved T cells function and would alleviate inflammation. We will establish cause and effect by manipulating mitoSTAT3 using genetic and pharmacological gain-and-loss of function approaches. This mechanistic work will map the role of mitoSTAT3 in the regulation of T cell metabolism and inflammation during aging and has therapeutic implications towards the goal of improving health span. .