Metabolic Dysfunction

项目1：细胞衰老和代谢功能障碍--Kirkland/Tchkonia摘要 衰老和肥胖都是2型糖尿病的主要危险因素，与衰老细胞堆积有关。 脂肪和其他组织中的毒素。在肥胖的小鼠中，我们发现衰老的细胞释放胰岛素抵抗诱导 因子并吸引和锚定炎症免疫细胞，放大代谢功能障碍；但已得到缓解 通过减少衰老的细胞负担，从基因上或通过抗衰老药物。我们的假设是以衰老为目标 细胞可以缓解与年龄相关的代谢功能障碍及其并发症。是否有类似的机制 在与年龄相关的代谢功能障碍中操作必须进行测试。我们的目标是发现和开发干预措施 它的目标是衰老细胞，以减少与年龄相关的代谢功能障碍。目标1是描绘分子 衰老细胞引起代谢功能障碍并由其诱导的机制。通过测试哪一个 代谢功能障碍的代谢相关诱导物和介体会导致细胞衰老，我们将：AS- 确定细胞类型、诱导衰老的方式以及代谢和炎性物质的作用- 调节剂对脂肪组织细胞衰老相关分泌表型(SASP)的影响 影响已建立的脂肪组织衰老细胞中SASP的因素；阐明SASP对 脂肪生成和胰岛素反应性；使用在肥胖中成功的方法识别引起SASP的因素。 并测试脂肪细胞本身是否会变得像衰老一样并获得SASP。目标2是确定细胞- 衰老细胞参与代谢功能障碍的小叶机制。序列和仓库- 我们将研究脂肪组织衰老和免疫细胞随年龄增长的相关性。我们会 检测不同细胞类型和不同诱导剂诱导衰老的细胞在代谢紊乱中的作用。 建立一种新的衰老细胞移植方法，以明确衰老细胞在体内的作用机制。 进食新陈代谢压力。我们将在正在移植的衰老细胞中消除关键的SASP因素，并 比较小鼠和大鼠移植细胞的效果。目标3是确定和优化干预措施，使- ATE衰老相关代谢功能障碍及其并发症。我们将测试脂肪的贡献- 以衰老为特征的细胞、衰老的前脂肪细胞、内皮细胞和免疫细胞对年龄相关的代谢反应 利用转基因小鼠(LOX-ATTAC)消除衰老细胞的BOLIC功能障碍 和时间选择性。我们将使用INK-和p21-ATTAC小鼠来区分p16INK4a和p21Cip1的作用。这个 在第二个物种中，细胞衰老在年龄相关代谢功能障碍中的作用将在墨水中进行测试- Attac大鼠模型。由Core B开发的新化合物、给药间隔和感受性药物组合物的影响。 关于年龄相关代谢功能障碍的结合将首先在一种新的脂肪组织移植系统中进行测试，并 然后是各种年老的动物。现有的和新型的感觉剂对代谢和脂肪组织的影响将被综合考虑。 对比了项目2-4中对骨骼、心血管系统和肌肉的影响。

PROJECT 1: Cellular Senescence and Metabolic Dysfunction – SUMMARY Kirkland/Tchkonia Aging and obesity, both leading risk factors for type 2 diabetes, are associated with senescent cell accumula- tion in adipose and other tissues. In obese mice, we found senescent cells release insulin-resistance-inducing factors and attract and anchor inflammatory immune cells, amplifying metabolic dysfunction; yet was alleviated by reducing, genetically or with senolytics, senescent cell burden. Our hypothesis is that targeting senescent cells can alleviate age-related metabolic dysfunction and its complications. Whether analogous mechanisms operate in age-related metabolic dysfunction must be tested.. Our goal is to discover and develop interventions that target senescent cells to decrease age-related metabolic dysfunction. Aim 1 is to delineate the molecular mechanisms through which senescent cells cause and are induced by metabolic dysfunction. By testing which metabolically-relevant inducers and mediators of metabolic dysfunction cause cellular senescence we will: as- certain the role of cell type, means through which senescence is induced, and metabolic and inflammatory me- diators on the senescence-associated secretory phenotype (SASP) in adipose tissue cells;.test effects of factors on the SASP in already established adipose tissue senescent cells; elucidate effects of the SASP on adipogenesis and insulin responsiveness; identify causal SASP factors using approaches successful in obesi- ty; and test if fat cells themselves can become senescent-like and acquire a SASP. Aim 2 is to determine cel- lular mechanisms through which senescent cells contribute to metabolic dysfunction. Sequences and depot- dependence of adipose tissue senescent and immune cell accumulation with aging will be examined. We will test the role of different cell types and cells made senescent by various inducers on metabolic dysfunction us- ing a novel senescent cell transplant method to pinpoint mechanisms through which senescent cells accentu- ate metabolic stress. We will knock down key SASP factors in the senescent cells being transplanted and compare effects of transplanted cells in mice vs. rats. Aim 3 is to identify and optimize interventions that allevi- ate senescence-related metabolic dysfunction and its complications. We will test the contributions of adipo- cytes featuring senescence, senescent preadipocytes, endothelial cells, and immune cells to age-related meta- bolic dysfunction using transgenic mice (LOX-ATTAC) from which senescent cells can be removed with spatial and temporal selectivity. We will distinguish roles of p16Ink4a vs. p21Cip1 using INK- and p21-ATTAC mice. The role of cellular senescence in age-related metabolic dysfunction in a second species will be tested in an INK- ATTAC rat model. Effects of new compounds developed by Core B, dosing intervals, and senolytic drug com- binations on age-related metabolic dysfunction will be tested first in a novel adipose tissue explant system and then various aged animals. Metabolic and adipose tissue effects of existing and novel senolytics will be com- pared to effects on bone, the cardiovascular system, and muscle in Projects 2-4.