School of Sport, Exercise and Rehabilitation (SportExR) DMT PhD Programme

The inevitable, gradual loss of physical function with increasing age restricts the ability of older adults to perform activities of daily living, which in turn impacts heavily on their independence and quality of life. The underlying causes of this loss of function are complex and multidimensional.

Sadly, the loss of physical function is exacerbated in some individuals to produce conditions such as frailty, but why this affects some more than others is unknown.

Regardless of the causes, the cost to society is large and increasing; according to Age UK frailty is seen in around 10% of all individuals over 65 and is characterised by a loss of strength and increased fatigue. These symptoms (and old age in general) are accompanied by many anatomical and physiological changes to the human body.

Two key changes that are clearly responsible for a loss of strength and associated loss of physical function are reductions in efficacy of i) skeletal muscle and ii) the nervous system (both central and peripheral).

As a result, the complex interaction between these two systems is also likely to be significantly disrupted, but this has not yet been extensively investigated. There is therefore an urgent need to understand the connection between these systems in the context of aging research.

Therefore, the overarching ambition of the proposed PhD projects will be to understand how changes along the whole central/peripheral nervous system/muscle axis occur with aging, and how these changes interact to produce weakness.

This holistic approach will take advantage of the complimentary expertise in neuroscience, neuromuscular and muscle physiology found in the School of Sport, Exercise and Rehabilitation Sciences.

Although a reduction in muscle mass is quite obviously responsible and crucially important for the loss of strength in old age, it does not tell the whole story.

Another key factor that may play a pivotal role in a loss of strength, may be neural hypoexcitability: an implicit loss, or lowering, of excitability in neural elements.

This reduced excitability can be seen at the level of the cortex, where motor evoked potentials (MEP; the size of an EMG burst triggered by a pulse transcranial magnetic brain stimulation (TMS)) are seen to be reduced in weak elderly subjects.

A similar lowering of neural excitability can be seen in peripheral neural elements, such as a lowering of motor unit firing rates during contraction.

Though the latter is a keen example of the complex body/brain interaction as motor unit firing rates can be modulated by both central (cortex brain stem, spinal cord) and peripheral pathways (muscle spindle, tendon-organ and innervated fibres). Currently, how each of these mechanisms contribute to weakness in the old is unknown.

The mechanisms outlined above in no way downplay the role of loss of muscle mass and muscle quality in functional decline with ageing.

Resistance to anabolic stimuli such as nutrition and exercise undoubtedly are key contributors to loss of physical function through muscle protein imbalance and reduced type II muscle fibre size.

This age-related anabolic resistance (and sarcopenia progression in general) has been linked to physical inactivity and disuse.

As well, reductions in the energetic potential of ageing muscle (i.e., mitochondrial dysfunction), altered redox balance and increased inflammation may contribute to disturbances in muscle protein balance in addition to directly impairing fatigue resistance.

Crucially, these peripheral metabolic factors have largely been studied in isolation from central and peripheral neural inputs and interdisciplinary collaborative efforts are now required to address key knowledge gaps.

Considering the above, we plan for the 4 PhD students recruited to this program to conduct carry out their research under the following separate but overlapping areas: • Exploring the role of neural excitability as a modulator of physical function across the life-course. • Investigating central and peripheral contributions to motor unit firing and physical function across the life-course. • Determining a role for nutrition in the modulation of neural excitability and neuromuscular drive. • Delineating the influence of changes neural excitability and neuromuscular drive on muscle anabolic potential in old age.

Initial outcomes will be interpreted in an integrative manner and our aim is to use the better understanding of the individual contribution of the neural and muscular elements, and crucially the complex interplay between them, to inform and investigate improved interventions. Classically interventions are designed around one modality i.e., a supplement, or exercise training regime.

Given the hypothesis that the symptoms themselves are the product of more than one system, we think that our programme of work will reveal interactions that can be exploited to improve interventions beyond a sum of their parts.

For example, combining interventions which are known to increase muscle mass (i.e. resistance training/ specific aspects of protein nutrition) with other interventions which are known to enhance CNS drive (skill training/brain stimulation).

This work will harness the unique expertise that is available in the School, to ultimately develop interventions with the potential to maximise impact by stimulating both central and peripheral pathways to delay or even reverse the age-related loss of function.

Thus, we propose an integrative PhD programme to study the whole CNS-muscle axis in concert to attain individual and collective contributions on the component parts.

We will use the mechanistic insights to investigate plausible interventions (for example combinations of targeted nutrition, brain stimulation, exercise, and physiotherapy) that may help delay or recover loss of physical function in older adults.

The program of work will include cross-sectional studies with cohorts of young, middle-aged, healthy-old, and frail-old as well as experimental models of accelerated muscle and strength loss e.g., immobilization studies in young and inactivity studies in older adults.