Preserving musculoskeletal mass and function with age is important to strength, power and endurance, as well as metabolic health. Physical activity decreases with age, contributing significantly to loss of musculoskeletal mass and function which limit activities of daily living.
Switching to a more physically active lifestyle in older individuals could ameliorate this deterioration, but adoption of such changes is notoriously difficult to achieve.
In addition, large individual differences in the rate of musculoskeletal ageing suggest that endogenous factors have a significant impact and the Centre will focus on the role of the age-related increase in inflammatory status.
The Centre is delivering five complementary programmes of research to develop a comprehensive understanding of age-related musculoskeletal deterioration in humans, using integrative physiology, molecular biology and systems biology approaches to identify primary drivers of decline.
Novel interventions, both lifestyle (diet and exercise) and pharmacological will be evaluated and for lifestyle interventions significant effort will be placed upon developing protocols which achieve good uptake and adherence by older adults.
Mechanisms of Musculoskeletal Ageing...
We place particular emphasis on:
Anabolic blunting: Building on our discovery of anabolic resistance in older people , i.e. blunted stimulation of muscle protein synthesis and impaired inhibition of breakdown following eating, we will perform clinical studies giving us crucial molecular and tissue-level insights into this process, providing clues how to overcome it in population-level interventions.
Increased adiposity and sarcopenia: Subcutaneous and visceral adipose tissue increases with age leading to hypertriglyceridemia and elevated inflammatory cytokines and adipokines, which contribute to skeletal muscle insulin resistance. We will explore the mechanisms of these processes at a molecular and cellular level.
Muscle microvascular blood flow: Obesity and the metabolic syndrome lead to microvascular endothelial function loss in muscle before macrovascular impairments are evident , and our clinical studies, including interventions, will all build from and further contribute to our expertise and understanding in this area.
Endocrine disruption: Cushing’s syndrome provides a paradigm for the ageing process: circulating glucocorticoid excess leading to sarcopenia, osteoporosis, central obesity and diabetes. We believe that physical activity and healthy weight can reverse and stabilise hormonal signals, and will be further probing the mechanisms underlying these changes in the ageing population.
Age-related neurodegeneration occurs in both motor and cognitive neurones. Loss of cognitive function is accelerated by age-related reduced physical activity, obesity and inflammation, with exercise interventions giving substantial improvement. The large artery and microvascular endothelial impairments associated with inflammation and ageing may also reduce local blood perfusion in the central nervous system.
Core studies within will define the influence of ageing, physical activity levels and age-induced inflammation on neuromuscular impairments, particularly on neuromuscular fatigue, balance and fall risk, perception-action coupling, reaching and grasping and motor control. By addressing the relationship between perception, control, learning and behaviour in these contexts, we can deliver hugely beneficial advances in the activity capabilities, and therefore musculoskeletal health, of older adults.
Systems Biology of Musculoskeletal Ageing...
Our Centre will provide a systems-level understanding of the effects of ageing on the musculoskeletal system, to identify biomarkers and novel targets for intervention. The projects under this umbrella will allow the development of a computational model of ageing human muscles, encompassing the interaction between inflammatory and endocrine signals driving response to stimulation with the control of bioenergetic functions.
Developing further on existing collaborations (e.g. the FP7 project Synergy
(http://www.synergy-copd.eu/), part of the Virtual Physiological Human initiative) and databases (e.g. the GEO database (http://www.ncbi.nlm.nih.gov/geo/)), we can develop models representing physiological and pathological adaptation mechanisms. We will also pursue the role of epigenetic modifications in ageing muscle, and examine the metabolomics of ageing muscles, as well as developing biomarkers of ageing muscles and cachexia, capturing the variation in response to exercise , nutritional and pharmacological interventions in young and old volunteers.
Interventions to Reduce Musculoskeletal Ageing:...
The interventional strand of our research has the capability to deliver enormous value for public health, focusing on clinical studies in human populations to ensure that research outcomes can be effectively and efficiently translated into patient benefit as quickly as possible. These will be based around:
Exercise strategies: We will test the benefits, mechanisms and best applications of low load eccentric resistance exercise training (RET), known to be more effective than conventional resistance training at increasing muscle mass and strength in older people, and high intensity interval training (HIT), which requires only a fraction of the time commitment of current exercise guidelines yet improves muscle microvascular density and function, arterial health, oxidative capacity and insulin sensitivity in young sedentary males. These novel exercise interventions will be extended to older people to counteract sarcopenia and osteoporosis and sustain vascular metabolic health.
Diet and Nutrition: The metabolic benefits of weight loss are clear. In collaboration with the Centre for Obesity Research (http://www.birmingham.ac.uk/obesity) we will define the impact of structured, supervised weight loss on musculoskeletal mass, function and the molecular adaptation in muscle in overweight elderly subjects. Personalised calorie restricted diet plans will be incorporated along-side behavioural strategies, as well as studies around novel uses of existing dietary supplements.
Pharmacological interventions: The Centre will probe how best to target endocrine and cytokine modulation and their contribution to ‘healthy’ and ‘unhealthy’ musculoskeletal ageing through pharmacological agents in collaboration with existing pharmaceutical partners, both for new agents and for existing agents which may be repurposed or demonstrate additional therapeutic value.
Healthy Lifestyle Adoption...
The benefits of regular physical activity and the consumption of a ‘healthy’ diet (in terms of caloric balance and intake of macro- and micro-nutrients) for quality of life, prevention of obesity, and reduction in chronic disease risk are clear. However, a considerable percentage of adults in the UK engage in neither. Our own past work and that of others has shown the importance of theory in developing, implementing and evaluating interventions centred on promoting active living and well-being, from one-on-one and small group interventions in exercise on referral schemes, to community exercise classes and workplace wellbeing programmes .
We are extending this into clinical settings with older patients, using not only motivational theory but advancements in mobile technology. Notably, simple interventions around point-of-choice prompting can deliver huge benefits at a population level for very modest cost. We will be developing a prototype exercise consultation for physical activity promotion in clinical populations that considers variability based on gender, age, culture/ethnicity, and health status.