Discovering mechanisms of tissue-resident immune aging

项目摘要 持续的低级别炎症是慢性疾病发展的基础，慢性疾病在 老年人。脂肪组织对年龄相关的炎症表现出独特的易感性。即使是健康的人 在老年时积累内脏脂肪，导致全身炎症增加和代谢减少 健康。老年人脂肪组织炎症的一个强有力的候选来源是常驻免疫隔室。 在每个器官中都有一个特殊的常驻免疫细胞库，这对组织的动态平衡至关重要 和压力适应。在脂肪组织中，常驻免疫细胞协调对禁食和寒冷的反应，并且 我们之前的工作证实，脂肪驻留免疫细胞的变化会损害对这两种情况的反应 老年小鼠面临的挑战。但在整个过程中，驱动脂肪驻留免疫功能障碍的机制 寿命仍然难以捉摸。这项提议将利用新的技术方法来解决这个问题。 悬而未决的问题。外周免疫细胞在衰老过程中积累细胞内缺陷，导致较差 接种疫苗或感染后的免疫保护。鉴于组织驻留的免疫细胞在生命早期就被播种 并通过自我更新来维持，我们预计他们对与年龄相关的监管特别敏感 压力。重要的是，免疫细胞也对环境信号敏感，细胞外细胞因子和 营养的可获得性强烈影响免疫细胞的招募和功能。因此，我们假设 免疫细胞的内在和外在机制都会导致衰老脂肪驻留的失调 免疫舱。我们将使用可诱导的命运映射策略，结合血管内标记， 研究真正的长寿脂肪驻留免疫细胞。我们将使用基于病毒载体的邻近连接 发现脂肪分泌蛋白随年龄变化并测试其对居民影响的方法 免疫细胞。通过比较老年和年轻肥胖小鼠，我们将分离年龄特定的肥胖小鼠的机制 炎症和脂肪组织功能障碍。我们将利用这些结果制定新的战略，以保护 延缓衰老的脂肪免疫隔膜，预防炎症。我们的方法克服了几个 衰老科学的长期障碍：(1)了解免疫细胞的“年龄”；(2)准确定位已知细胞 与年龄相关的细胞因子/分泌因子的来源。有了这些新的能力，我们的工作将会取得进展 衰老科学，并使发现影响任何器官系统的新疾病机制成为可能。

Project Summary Persistent low-grade inflammation underlies the development of chronic diseases that are prevalent in the elderly. Adipose tissue displays unique susceptibility to age-related inflammation. Even healthy individuals accumulate visceral adiposity in older age, leading to increased systemic inflammation and reduced metabolic health. A strong candidate source of inflammation in aged adipose tissue is the resident immune compartment. Within every organ is a specialized repertoire of resident immune cells that is essential for tissue homeostasis and stress adaptation. In adipose tissue, resident immune cells coordinate responses to fasting and cold, and our prior work establishes that changes in adipose-resident immune cells impairs responses to both these challenges in old mice. But the mechanisms that drive adipose-resident immune dysfunction throughout the lifespan have remained elusive. This proposal will leverage new technological approaches to address this outstanding question. Peripheral immune cells accumulate intracellular defects during aging, leading to poor immune protection after vaccination or infection. Given that tissue-resident immune cells are seeded early in life and maintained through self-renewal, we expect them to be especially sensitive to age-related regulatory pressures. Importantly, immune cells are also sensitive to environmental cues, and extracellular cytokines and nutrient availability strongly influence the recruitment and function of immune cells. Therefore, we hypothesize that both immune cell-intrinsic and -extrinsic mechanisms cause dysregulation of the aging adipose-resident immune compartment. We will use an inducible fate-mapping strategy, combined with intra-vascular labeling, to study bonafide long-lived adipose-resident immune cells. We will use a viral vector-based proximity ligation approach to discover age-dependent changes in adipose secreted proteins and test how they impact resident immune cells. By comparing old and younger obese mice, we will isolate age-specific mechanisms of inflammation and adipose tissue dysfunction. We will use these results to develop new strategies that protect the aging adipose-resident immune compartment and prevent inflammation. Our methods overcome several longstanding obstacles in aging science: (1) knowing the “age” of an immune cell, and (2) pinpointing known cell sources of age-associated cytokines/secreted factors. With these new capabilities, our work stands to advance aging science and enable discovery of new disease mechanisms affecting any organ system.