MtDNA variant modifiers of cardiopulmonary responsiveness to physical activity

The prevalence of cardiovascular disease will rise as life expectancy of older Americans continues to increase, with persons aged >75 years representing the fastest growing segment of the US population. Low physical fitness is a major pathway leading to poor cardiopulmonary function that is primarily caused by engaging in a sedentary lifestyle. As such, increasing physical activity remains a priority for meeting these public health challenges, especially in older adults who harbor the greatest risk of chronic health conditions. While it is generally recognized that physical activity is beneficial for adults regardless of age, sex, race/ethnicity, or health status, the cardiopulmonary responsiveness is highly variable and therefore not everyone realizes a benefit, which others respond more favorably than expected. Based on our previous observation that both common and rare nonsynomymous mitochondrial DNA (mtDNA) variants are associated with physical activity energy expenditure and cardiopulmonary measures, we postulated that these variants are likely to identify cardiopulmonary responsiveness to chronic physical activity. To that end, our central hypothesis is that mtDNA sequence variation explains a portion of the heterogeneity in cardiopulmonary responsiveness to chronic physical activity. We have a unique opportunity to test our central hypothesis in an efficient and cost-effective manner by sequencing the entire 16.5kb of mtDNA in stored samples of participants in the Lifestyle Interventions and Independence for Elders Study (The LIFE study). The LIFE study is a definitive Phase 3 multicenter single-masked RCT to evaluate a physical activity program vs. a successful aging health education program. The study has an average follow-up duration of approximately 2.7 yrs (range 1.9-3.7 yrs) in 1,592 community-dwelling sedentary persons age 70-89 yrs with stored genetic material. The completed LIFE Pilot study— a cohort of 396 participants randomized to the same interventions for 12 months— will be used to replicate significant associations. Our hypotheses focus on mtDNA, which has a mutation rate that is 10-20 times higher than that of nuclear DNA and up to one-third of sequence variants found in the general population are functionally important. The proposed work examines interactions in both common and rare mtDNA variants on responsiveness to the following cardiopulmonary measures: 1) walking speed, 2) blood pressure and 3) lung function that are being collected as part of the trial. We will integrate clinical, behavioural and genetic data in models to predict the heterogeneity in cardiopulmonary responsiveness to physical activity.