Abstract: Obesity causes serious medical complications and impairs quality of life. Moreover, in elderly persons, obesity can lead to frailty by exacerbating the decline in strength, endurance, balance and mobility associated with aging and physical inactivity. Appropriate treatment for obesity in elderly persons is controversial because of the decreased relative health risks with increasing body mass index in the elderly and the potential harmful effects of weight loss on bone health and muscle mass. The primary objectives of the proposed research are to evaluate the independent and combined effects of weight loss and exercise on physical function, body composition, bone and muscle metabolism, and quality of life in frail, obese elderly men and women. The central hypothesis is that in frail obese elderly subjects, weight loss will improve physical function and quality of life, while the addition of exercise will not only augment improvement in these outcomes, but also attenuate the adverse effects of weight loss on bone and muscle masses. To test this hypothesis, 100 elderly (65-85 years old) obese men and women (BMI >30 kg/m2) with physical frailty will be randomized to 4 treatment groups: 1) control, 2) 10% weight loss, 3) exercise training, and 4) 10% weight loss plus exercise training. Measures of physical function (physical performance test, performance-based tests of strength, flexibility, endurance, balance, and motor control, and questionnaires that evaluate functional status), body composition (total body fat and fat-free mass evaluated by dual energy x-ray absorptiometry, abdominal fat and thigh muscle mass measured by magnetic resonance imaging), bone mineral density (BMD) and bone turnover (total body and regional BMD in conjunction with markers of bone formation and resorption), muscle protein synthesis (myofibrillar protein synthesis rate using stable isotope tracer techniques), and health related quality-of-life (Short-Form Health Survey and Impact of Weight on Quality of Life questionnaires) will be determined before, during, and after a 52-week treatment intervention. Subjects randomized to weight loss and weight loss plus exercise group will participate in a comprehensive weight management program at the Washington University Weight Management Center. Subjects randomized to exercise or weight loss plus exercise will participate in a supervised exercise-training program (90-min sessions, 3 days/week for 52 weeks). Encouraging results from a 1-year pilot study suggest the feasibility and efficacy of a lifestyle modification program towards improving physical function in frail obese elderly subjects. The data generated from this proposed randomized controlled trial will ultimately establish appropriate treatment guidelines for the increasing number of frail obese elderly men and women.