ESTABLISHING THE ROLE OF ADIPOSE TISSUE INFLAMMATION IN THE REGULATION OF MUSCLE MASS IN OLDER PEOPLE

世界上每一个国家的老年人在其人口中的规模和比例都在增长。联合国认识到这一趋势，将2021年至2030年定为联合国健康老龄化十年，旨在促进合作努力，使个人能够活得更长，更健康。老龄化带来的主要社会挑战之一是骨骼肌的丧失，这导致虚弱，脆弱和失去独立性。导致肌肉损失和虚弱的一个关键因素是慢性低度炎症-但这种炎症的主要来源一直不确定。脂肪组织（身体脂肪）现在被认为是一个重要的和相当大的免疫器官。我们的初步工作表明，在一些老年人中，脂肪组织发炎并分泌大量促炎分子。我们发现，从脂肪组织中分泌的一种分子（IL-8）可以预测老年人肌肉质量的两种独立测量方法（全身DEXA扫描和腿部CT扫描）。这些新的发现得到了流行病学研究的支持，这些研究报告说，IL-8是英国成年人肌肉质量低的一个强有力的预测因子，以及使用细胞模型的研究表明，IL-8会损害肌肉细胞的生长。基于这些初步发现，我们假设脂肪组织是衰老中炎症的主要来源（在没有肥胖的情况下），并且老年人脂肪组织中IL-8（以及潜在的其他类似分子）的高分泌对肌肉蛋白质代谢和维持肌肉质量的能力产生负面影响。为了验证这一假设，我们建立了一个由脂肪组织生物学和骨骼肌蛋白质代谢专业人员组成的合作团队。我们设计了一系列体内和体外实验，以确定脂肪组织炎症是否是老年人肌肉蛋白质代谢的重要驱动因素。对于我们的人体研究，我们将招募具有不同水平脂肪组织炎症（高/低）的老年男性和女性，通过注入示踪剂（稳定的同位素标记氨基酸）和进行肌肉活检，我们将能够评估体内全身和肌肉蛋白质代谢（在休息时，以及对运动和营养刺激的反应）。我们将使用最先进的技术来检查衰老中脂肪组织炎症所涉及的细胞和途径-我们将确定老年人发炎脂肪组织分泌的蛋白质的类型（和数量）。我们将通过细胞培养研究来支持体内观察，以检查脂肪组织分泌的分子对体外生长的肌肉细胞的直接影响。这些细胞研究还将使我们能够检查被激活/抑制的不同途径，以及是否有可能阻断对骨骼肌生长调节产生负面影响的途径。最后，在本项目结束时，我们将建立一个独特的生物库，以支持未来的成本效益研究，包括本项目期间收集的数据（例如，肌肉蛋白质合成）以及获得匹配的生物样品。该项目为新型靶向干预和治疗铺平了道路，以避免炎症介导的骨骼肌损失和衰老脆弱。例如，如果我们发现IL-8在衰老过程中对骨骼肌质量的调节非常重要，那么未来的研究可以检查基于抗体的治疗（即，抗IL-8）增加肌肉质量或防止老年人特定群体的下降。总的来说，该项目将确定脂肪组织在老年人肌肉质量调节中的作用，并为新的干预和治疗奠定基础-以及通过访问大量数据集和相关生物样本支持其他与年龄相关的研究。

Every country in the world is experiencing growth in both the size and the proportion of older people in their populations. In recognition of this trend, the United Nations has designated 2021 to 2030 as the UN Decade of Healthy Ageing, with the aim of promoting collaborative efforts to enable individuals to live longer and healthier lives. One of the main societal challenges from ageing is loss of skeletal muscle which leads to weakness, frailty, and loss of independence. A key factor that leads to muscle loss and weakness is chronic low-grade inflammation - but the primary source of this inflammation has always been uncertain. Adipose tissue (body fat) is now recognised as an important and sizeable immunological organ. Our preliminary work demonstrates that, in some older people, adipose tissue becomes inflamed and secretes large amounts of pro-inflammatory molecules. We found that the secretion of one molecule from adipose tissue (IL-8) was predictive of two independent measures of muscle mass in older people (a whole-body DEXA scan, and a leg CT scan). These new findings are supported by epidemiological studies which report that IL-8 is a strong predictor of low muscle mass in UK adults - as well as studies using cell models which show that IL-8 impairs muscle cell growth. Based on these preliminary findings, we hypothesise that adipose tissue is a major source of inflammation in ageing (in the absence of obesity), and that high secretion of IL-8 (and potentially other similar molecules) from adipose tissue in older people negatively affects muscle protein metabolism and the ability to maintain muscle mass. To examine this hypothesis, we have established a collaborative team of researchers with expertise in adipose tissue biology and skeletal muscle protein metabolism. We have designed a series of in vivo and in vitro experiments to establish if adipose tissue inflammation is an important driver of muscle protein metabolism in older people. For our human studies, we will recruit older men and women with different levels of adipose tissue inflammation (high/low) and, by infusing tracers (stable isotopically labelled amino acids) and taking muscle biopsies, we will be able to assess whole-body and muscle protein metabolism in vivo (at rest, and also in response to stimulation with exercise and nutrition). We will use state-of-the-art techniques to examine the cells and pathways that are involved in adipose tissue inflammation in ageing - and we will identify the types (and amount) of proteins that are secreted by inflamed adipose tissue in older adults. We will support in vivo observations with cell culture studies to examine the direct effects of the molecules secreted by adipose tissue on muscle cells grown in vitro. These cell studies will also allow us to examine the different pathways that are activated/inhibited, and whether it is possible to block pathways which are negatively impacting the regulation of skeletal muscle growth. Finally, at the end of this project, we will set up a unique biobank to support future cost-effective research, comprising the data collected during this project (e.g., Muscle Protein Synthesis) alongside access to matched biological samples. This project paves the way for novel targeted interventions and therapies to avoid inflammation-mediated loss of skeletal muscle and frailty with ageing. For example, if we find that IL-8 is pre-eminently important in the regulation of skeletal muscle mass in ageing, then future studies could examine whether antibody-based therapies (i.e., anti-IL-8) increase muscle mass or prevent decline in specific groups of older people. Collectively, this project will establish the role of adipose tissue in the regulation of muscle mass in older people and lay the foundation for novel interventions and therapies - as well as supporting other age-related research via access to substantial datasets and associated biological samples.