Discovering mechanisms of tissue-resident immune aging

项目概要 持续的低度炎症是慢性疾病发展的基础，这些慢性疾病普遍存在于 老人。脂肪组织对与年龄相关的炎症表现出独特的敏感性。即使是健康的人 老年时内脏脂肪堆积，导致全身炎症增加和代谢减少 健康。老化脂肪组织中炎症的一个强有力的候选来源是常驻免疫区室。 每个器官内都有一组专门的常驻免疫细胞，这对于组织稳态至关重要 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 我们之前的工作表明，脂肪驻留免疫细胞的变化会损害对这两种疾病的反应 年老小鼠面临的挑战。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。该提案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，导致免疫功能低下 接种疫苗或感染后的免疫保护。鉴于组织驻留免疫细胞是在生命早期播种的 并通过自我更新来维持，我们预计它们对与年龄相关的监管特别敏感 压力。重要的是，免疫细胞对环境信号、细胞外细胞因子和 营养物质的可用性强烈影响免疫细胞的招募和功能。因此，我们假设 免疫细胞内在和外在机制都会导致衰老脂肪居民的失调 免疫室。我们将使用诱导命运图谱策略，结合血管内标记， 研究真正的长寿脂肪免疫细胞。我们将使用基于病毒载体的邻近连接 发现脂肪分泌蛋白的年龄依赖性变化并测试它们如何影响居民的方法 免疫细胞。通过比较老年和年轻的肥胖小鼠，我们将分离出年龄特异性机制 炎症和脂肪组织功能障碍。我们将利用这些结果来制定新的策略来保护 老化的脂肪驻留免疫室并预防炎症。我们的方法克服了几个 衰老科学中长期存在的障碍：（1）了解免疫细胞的“年龄”，以及（2）精确定位已知细胞 与年龄相关的细胞因子/分泌因子的来源。有了这些新功能，我们的工作就会取得进展 衰老科学可以发现影响任何器官系统的新疾病机制。

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.