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

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.