Grant: Operating Grant

Endurance exercise has been associated with lower risk of death, cancer, functional decline and cardiovascular disease in large human epidemiological studies. The fundamental mechanism(s) behind this multi-systemic effect in humans is not clear; however, in muscle there is evidence that this is due to an improvement of mitochondrial function (powerhouse of the cell). We have a mouse model of primary mitochondrial dysfunction that shows essentially all of the characteristic features of human aging and recently demonstrated substantial clinical protection from the aging features in this mouse with long term endurance exercise. We plan on following up on this important pilot data with a series of experiments designed to understand the potential biological mechanisms that lead to such profound protective effects in skeletal muscle, heart, brain, skin and even the bone marrow. To this end, we will compare and contrast the influence of endurance exercise in our mitochondrial dysfunction mice (polymerase gamma mutator mice) as compared to wild type (normal) mice. We will evaluate important questions such as the possibility that exercise early in life may confer protective benefits later in life even if the exercises stopped. We will also determine whether voluntary exercise has some of the same benefits as forced endurance exercise. Although our main emphasis will be on a mechanistic evaluation of the impact of endurance exercise and primary mitochondrial dysfunction in skeletal muscle, we will also evaluate a variety of other tissues with secondary emphasis on the heart and brain given the importance of these organs in aging associated morbidity in older adults. The results of this study will lead to a better understanding of the protective effects of exercise and also identify a variety of biological targets that may be amenable to nutritional or pharmaceutical intervention in the future for those who cannot exercise.