Obesity and metabolic disorders have become a notable world-wide epidemic. The pathogenesis of metabolic diseases, such as metabolic syndrome and type 2 diabetes, has begun to negatively affect life expectancy of current generations. Low aerobic capacity has shown to be a strong predictor of mortality both in rodents and humans. Exercise is known to increase an individual’s aerobic capacity; interestingly, recent studies have suggested that genetic background may play a significant role in the physical activity level of an individual. The purpose of this study was to investigate the role of genetic background and physical activity on skeletal muscle properties, metabolism and lifespan. The study consisted of three parts: (1) a cross-sectional voluntary running intervention in high-capacity runner (HCR) and low-capacity runner (LCR) rats, (2) a longitudinal voluntary running intervention in HCR and LCR rats, and (3) a long- term follow-up study with physical activity discordant human twins. Our study showed that low intrinsic aerobic capacity is associated with fast muscular fatigue and slow metabolic recovery after maximal muscle contractions. At the whole- body level, low intrinsic aerobic capacity was linked to low body temperature, which may play a role in the onset of gaining extra weight and, thus, developing metabolic disorders. High intrinsic aerobic capacity in turn was associated with elevated SIRT3 protein level in skeletal muscle, which is possibly linked to increased lifespan. Nevertheless, vigorous physical activity commenced at adult age did not reduce mortality or increase lifespan in rodents. High long-term participation in vigorous leisure-time physical activity did predict significantly reduced mortality in dizygotic twins; however, there was no difference in the lifespan of monozygotic twins that are genetically identical. HCRs were more physically active both in control and voluntary running groups when compared to corresponding LCR groups. Also, the persistent discordances in participation of vigorous physical activity were significantly more common in dizygotic twin pairs than in monozygotic pairs stating that genes have an influence on the persistent voluntary participation in vigorous leisure-time physical activity. Our results indicated that genetic predisposition plays a significant role in exercise participation, hence, genetic pleiotropy may partly explain the associations observed previously between high physical activity and mortality.