The ability to sustain muscular exercise is a key determinant of health, quality of life, and mortality. A low tolerance for exercise contributes to a downward spiral of inactivity, which is debilitating in the elderly and an actual cause of many chronic diseases. Therefore, a better understanding of the mechanisms that allow exercise to be sustained is central to our ability to help maintain health, quality of life and promote longevity. Sustaining muscular exercise depends on the body's ability to provide energy through 'oxidative', or aerobic, pathways. These are chemical reactions that synthesise energy through the consumption of oxygen. However, bodily stores of oxygen are very limited so at exercise onset the lungs, heart and muscles must respond in a coordinated fashion to transport oxygen from the atmosphere to where it is used in the active muscles. In healthy individuals the required increases in pulmonary ventilation, cardiac output, muscle blood flow, and muscle oxygen utilisation occur in a well coordinated fashion. However, to achieve this coordination the responses of these systems lag behind the energy demands by about 3 minutes in normal healthy subjects. The kinetics with which oxygen transport and utilisation can respond therefore determines whether or not the body is able meet the energy demands through oxidative pathways. Because demands for activity fluctuate throughout the day (e.g. walking, stair climbing, etc), the response kinetics of energy providing pathways have a significant impact on the ability to carry out the tasks of daily living. It is of considerable concern, therefore, that these response kinetics are very slow in the elderly, and take about twice as long to reach their requirement compared to young individuals. In the elderly therefore there is a greater high reliance on alternative routes of energy provision (termed anaerobic, because they don't consume oxygen). These are detrimental to exercise tolerance because they are related to increased muscle fatigue, shortness of breath and pain. It is perhaps unsurprising, therefore, that physiological systems respond very rapidly in trained athletes. The mechanisms that determine the integrated responses of the pulmonary, circulatory and muscular systems, however, are currently unresolved. The studies in this proposal aim to improve our understanding of the interactions between oxygen delivery to, and utilisation in, the active muscles during the transition from rest to exercise. A better understanding of how these processes work will improve our ability to address the slow oxygen consumption kinetics in the elderly, as well as the optimisation of these processes in elite athletes. The experiments for these studies are organised into three tracks: 1) studies to elucidate how the kinetics of muscle fatigue and oxygen uptake contribute to limiting exercise tolerance in young, elderly and endurance trained subjects; 2) studies to elucidate how rates of aerobic and anaerobic energy provision are distributed throughout the active muscles; and 3) studies to generate a computer model to simulate energy provision and integrated physiological systems integration during exercise over a variety of conditions. All the experiments are made using non-invasive measurements during leg exercise in young (<30 years), elderly (>65 years) or elite endurance trained athletes (volunteers from the Great Britain cycling squad). The outcomes of this project will improve our understanding of how the body responds to the energy demands of physical activity, and how the provision and utilisation of oxygen is optimised to allow high work rates to be sustained. These studies will therefore underpin the development of new strategies (either pharmacological or exercise based) for ameliorating the mechanisms limiting exercise tolerance in humans, and thereby contribute to the maintenance of health, quality of life, and longevity.