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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL121023-01
Application #
8614159
Study Section
Kidney, Nutrition, Obesity and Diabetes (KNOD)
Program Officer
Papanicolaou, George
Project Start
2014-01-15
Project End
2017-12-31
Budget Start
2014-01-15
Budget End
2014-12-31
Support Year
1
Fiscal Year
2014
Total Cost
$488,522
Indirect Cost
$49,545
Name
University of Florida
Department
Other Health Professions
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Rejeski, W Jack; Marsh, Anthony P; Brubaker, Peter H et al. (2016) Analysis and Interpretation of Accelerometry Data in Older Adults: The LIFE Study. J Gerontol A Biol Sci Med Sci 71:521-8
Wawrzyniak, Nicholas R; Joseph, Anna-Maria; Levin, David G et al. (2016) Idiopathic chronic fatigue in older adults is linked to impaired mitochondrial content and biogenesis signaling in skeletal muscle. Oncotarget :
Kheirkhahan, Matin; Tudor-Locke, Catrine; Axtell, Robert et al. (2016) Actigraphy features for predicting mobility disability in older adults. Physiol Meas 37:1813-1833
Fitzgerald, Jodi D; Johnson, Lindsey; Hire, Don G et al. (2015) Association of objectively measured physical activity with cardiovascular risk in mobility-limited older adults. J Am Heart Assoc 4:
Tranah, Gregory J; Yaffe, Kristine; Katzman, Shana M et al. (2015) Mitochondrial DNA Heteroplasmy Associations With Neurosensory and Mobility Function in Elderly Adults. J Gerontol A Biol Sci Med Sci 70:1418-24
Espeland, Mark A; Newman, Anne B; Sink, Kaycee et al. (2015) Associations Between Ankle-Brachial Index and Cognitive Function: Results From the Lifestyle Interventions and Independence for Elders Trial. J Am Med Dir Assoc 16:682-9
Anton, Stephen D; Woods, Adam J; Ashizawa, Tetso et al. (2015) Successful aging: Advancing the science of physical independence in older adults. Ageing Res Rev 24:304-27
Manini, Todd M (2015) Using physical activity to gain the most public health bang for the buck. JAMA Intern Med 175:968-9
Tranah, Gregory J; Yokoyama, Jennifer S; Katzman, Shana M et al. (2014) Mitochondrial DNA sequence associations with dementia and amyloid-β in elderly African Americans. Neurobiol Aging 35:442.e1-8
Pahor, Marco; Guralnik, Jack M; Ambrosius, Walter T et al. (2014) Effect of structured physical activity on prevention of major mobility disability in older adults: the LIFE study randomized clinical trial. JAMA 311:2387-96

Showing the most recent 10 out of 13 publications