Journal
CIRCULATION RESEARCH
Volume 109, Issue 10, Pages 1162-U151Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.111.253807
Keywords
exercise capacity; longevity; cardiomyocyte function; rat models; aging
Funding
- Department of Anesthesiology, University of Michigan Medical School
- National Center for Research Resources of the National Institutes of Health [R24 RR017718]
- Michigan Nutrition Obesity Research Center [DK 089503]
- Michigan Diabetes Research and Training Center [NIH5P60 DK20572]
- University of Michigan Institute of Gerontology, Nathan Shock Center [P30 AG013283]
- Geriatric Center
- National Institutes of Health [RO1 DK077200]
- Norwegian Council on Cardiovascular Disease
- Norwegian Research Council
- K.G. Jebsen Foundation
- Simon Fougner Hartmanns Family Foundation
- Foundation for Cardiovascular Research at St. Olav's Hospital
- British Heart Foundation
- The Claude D. Pepper Older Americans Independence Center [P30 AG013283]
- British Heart Foundation [PG/09/107/28154] Funding Source: researchfish
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Rationale: Low aerobic exercise capacity is a powerful predictor of premature morbidity and mortality for healthy adults as well as those with cardiovascular disease. For aged populations, poor performance on treadmill or extended walking tests indicates closer proximity to future health declines. Together, these findings suggest a fundamental connection between aerobic capacity and longevity. Objectives: Through artificial selective breeding, we developed an animal model system to prospectively test the association between aerobic exercise capacity and survivability (aerobic hypothesis). Methods and Results: Laboratory rats of widely diverse genetic backgrounds (N:NIH stock) were selectively bred for low or high intrinsic (inborn) treadmill running capacity. Cohorts of male and female rats from generations 14, 15, and 17 of selection were followed for survivability and assessed for age-related declines in cardiovascular fitness including maximal oxygen uptake (VO2max), myocardial function, endurance performance, and change in body mass. Median lifespan for low exercise capacity rats was 28% to 45% shorter than high capacity rats (hazard ratio, 0.06; P<0.001). VO2max, measured across adulthood was a reliable predictor of lifespan (P<0.001). During progression from adult to old age, left ventricular myocardial and cardiomyocyte morphology, contractility, and intracellular Ca2+ handling in both systole and diastole, as well as mean blood pressure, were more compromised in rats bred for low aerobic capacity. Physical activity levels, energy expenditure (Vo(2)), and lean body mass were all better sustained with age in rats bred for high aerobic capacity. Conclusions: These data obtained from a contrasting heterogeneous model system provide strong evidence that genetic segregation for aerobic exercise capacity can be linked with longevity and are useful for deeper mechanistic exploration of aging. (Circ Res. 2011;109:1162-1172.)
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