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. Poor physical fitness is a major contributor to poor cardiopulmonary function that is primarily caused by a sedentary lifestyle. Increasing physical activity remains a priority for improving cardiovascular health, especially in older adults, who are at the greatest risk of chronic health conditions. While it is generally recognized that physical activity benefits adults regardless of age, sex, race/ethnicity, or health status, the cardiopulmonary responsiveness varies greatly. Approximately 40% of people do not achieve a clinically meaningful benefit despite excellent adherence. On the other hand, 30% of people with poor adherence respond better than expected. Based on our previous observation that both common and rare nonsynonymous mitochondrial DNA (mtDNA) variants are associated with physical activity energy expenditure and cardiopulmonary outcomes, we postulated that these variants are likely to identify cardiopulmonary responsiveness to chronic physical activity. These data formed our central hypothesis 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 efficiently and cost-effectively 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 Randomized Controlled Trial that evaluates a physical activity program vs. a successful aging health education program. The average follow-up duration of the study is approximately 2.7 yrs, and the participants are 1,592 community-dwelling sedentary persons aged 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 address the effect of common and rare mtDNA variants on responsiveness to the following cardiopulmonary measures that are being collected as part of the trial: 1) walking speed, 2) blood pressure, and 3) pulmonary capacity. We will integrate clinical, behavioral, and genetic data in models to predict the heterogeneity in cardiopulmonary responsiveness to physical activity. By identifying genetic modifiers, this research will provide a starting point to build a personalized medicine framework to better improve cardiovascular health with physical activity. Identifying these genetic factors may also provide novel insights into the molecular pathways that regulate the cardiovascular adaptation to chronic physical activity. This approach could have a large impact in moving the field toward the NIH's goals of personalizing behavioral interventions for a rapidly aging America.

Public Health Relevance

The proposed research will discover genes that explain the variability in cardiopulmonary response to long- term physical activity- a widely accepted behavior known to influence many facets of health. This is highly relevant for personalizing lifestyle interventions to an individual's genetic makeup.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Kidney, Nutrition, Obesity and Diabetes (KNOD)
Program Officer
Papanicolaou, George
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Florida
Other Health Professions
Schools of Medicine
United States
Zip Code
Wanigatunga, Amal A; Manini, Todd M; Cook, Delilah R et al. (2018) Community-Based Activity and Sedentary Patterns Are Associated With Cognitive Performance in Mobility-Limited Older Adults. Front Aging Neurosci 10:341
Buford, Thomas W; Manini, Todd M; Kairalla, John A et al. (2018) Mitochondrial DNA Sequence Variants Associated With Blood Pressure Among 2 Cohorts of Older Adults. J Am Heart Assoc 7:e010009
Manini, Todd M; Buford, Thomas W; Kairalla, John A et al. (2018) Meta-analysis identifies mitochondrial DNA sequence variants associated with walking speed. Geroscience 40:497-511
Vaz Fragoso, Carlos A; Manini, Todd M; Kairalla, John A et al. (2018) Mitochondrial DNA variants and pulmonary function in older persons. Exp Gerontol 115:96-103
Tranah, Gregory J; Maglione, Jeanne E; Yaffe, Kristine et al. (2018) Mitochondrial DNA m.13514G>A heteroplasmy is associated with depressive symptoms in the elderly. Int J Geriatr Psychiatry 33:1319-1326
Tranah, Gregory J; Katzman, Shana M; Lauterjung, Kevin et al. (2018) Mitochondrial DNA m.3243A?>?G heteroplasmy affects multiple aging phenotypes and risk of mortality. Sci Rep 8:11887
Manini, Todd M; Anton, Stephen D; Beavers, Daniel P et al. (2017) ENabling Reduction of Low-grade Inflammation in SEniors Pilot Study: Concept, Rationale, and Design. J Am Geriatr Soc 65:1961-1968
Shadyab, Aladdin H; LaMonte, Michael J; Kooperberg, Charles et al. (2017) Leisure-time physical activity and leukocyte telomere length among older women. Exp Gerontol 95:141-147
Wanigatunga, Amal A; Tudor-Locke, Catrine; Axtell, Robert S et al. (2017) Effects of a Long-Term Physical Activity Program on Activity Patterns in Older Adults. Med Sci Sports Exerc 49:2167-2175
Valiani, Vincenzo; Sourdet, Sandrine; Schoeller, Dale A et al. (2017) Surveying predictors of late-life longitudinal change in daily activity energy expenditure. PLoS One 12:e0186289

Showing the most recent 10 out of 27 publications