Discovery of brain circuit reversing the decline in physical activity and muscle mass with age

Being physically active is one of the most important things we can do for our physical and mental health and yet, levels progressively decline with age. Without regular exercise, our muscles decrease in size and get weaker. This is important because the amount of muscle we have impacts quality of life, overall health and helps resist diseases, like type 2 diabetes and hypertension. The motivation gap to take up exercise programmes and stick with them has meant the health benefit of exercise is not available for many. In fact, approximately 40% of UK adults do not take the recommended minimum amount of exercise. How can we change this? The goal of this research programme is to identify a fundamental brain circuit controlling the motivation to be physically active. This programme of research is timely because how much people exercise is a key predictor for health and lifespan. We started by tracking steps using accelerometers in a group of younger and older UK adults and found the expected reduction in physical activity (PA) and muscle mass, and increase in fat mass in middle-aged compared to younger adults. We then asked why the motivation to exercise declines with age and turned our attention to brain function because it controls voluntary PA. We next surveyed changes that occur in the brain with age. A chemical made in our brain called serotonin is known to influence PA. We then performed a series of studies to support this application. Specifically, we found a certain subset of cells making serotonin in the brain region called the dorsal raphe nucleus (DRN) change their tone with ageing. We discovered that mimicking this serotonin:DRN tone in young mice produced a middle-aged PA profile. Importantly, we found that re-tuning the activity of serotonin cells only in this particular part of the brain completely reversed the decline in PA with ageing. In looking at how this might occur, we examined DRN serotonin cell communication with a brain region important for motivation and PA called the ventral tegmental area (VTA). We found that altering both the serotonin source and the receiver cells in middle-aged mice restored youthful PA levels. This research programme will establish the impact of this potential transformative discovery on PA over the lifecourse; defining whether this discrete brain serotonin source-receiver circuit drives the decline in PA with age and consequent loss of muscle mass, muscle function and associated health implications. We designed three objectives to probe this serotonergic brain circuit to establish whether manipulating its activity causes, restores and prevents the decline in PA and muscle characteristics with age. To achieve these objectives, we assembled a team of experts in brain serotonin, physical activity and muscle function. It has only now become possible to do these types of studies because of the latest technological advances. We expect that our results will provide a blueprint for future study and reveal a target for future interventions to promote healthy ageing. We believe the results generated by this fundamental research programme have the potential for future societal and economic impact. The identification of a discrete brain circuit where the tone of cells could be adjusted to foster greater PA could increase the number of healthy years lived for our ageing population.