Abstract
Large-scale epidemiological studies show that low exercise capacity is the highest risk factor for all-cause morbidity and mortality relative to other conditions including diabetes, hypertension, and obesity. This led us to formulate the energy transfer hypothesis (ETH): Variation in capacity for energy transfer is the central mechanistic determinant of the divide between disease and health. As a test of this hypothesis, we predicted that two-way selective breeding of genetically heterogeneous rats for low and high intrinsic treadmill running capacity (a surrogate for energy transfer) would also produce rats that differ for disease risks. The lines are termed low-capacity runners (LCRs) and high-capacity runners (HCRs) and, after 36 generations of selection, they differ by more than eightfold in running capacity. Consistent with the ETH, the LCRs score high for developing disease risks, including metabolic syndrome, neurodegeneration, cognitive impairment, fatty liver disease, susceptibility to cancer, and reduced longevity. The HCRs are resistant to the development of these disease risks. Here we synthesize ideas on nonequilibrium thermodynamics and evolution from Ilya Prigogine, Hans Krebs, and Peter Mitchell to formulate theoretic explanations for the ETH. First, at every moment in time, the atoms and molecules of organisms are reorganizing to pursue avenues for energy transfer. Second, this continuous organization is navigating in a constantly changing environment such that "strategies" are perpetually in flux and do not leave a simple footprint (evolution). Third, as a consequence, human populations demonstrate a wide variation in capacity for energy transfer that mirrors mechanistically the divide between disease and health.