Interrogating the age-old wisdom of exercise.

W e have long known that exercise is good for us. Hippocrates declared more than 25 centuries ago that " if we could give every individual the right amount of nourishment and exercise, not too little and not too much, we would have found the safest way to health. " There is now a wealth of evidence indicating that the benefits of physical activity extend across multiple organ systems and span the age spectrum. Perhaps most compelling are data highlighting the potential of exercise to prevent and attenuate chronic conditions related to insulin resistance and atherosclerosis. 3,4 Despite nationwide guidelines encouraging regular exercise for all adults, fewer than 1 in 3 Americans engage in routine physical activity. 5 Low adherence rates could relate in part to the fact that we still do not really understand how exercise works. For this reason , recommendations remain nonspecific with respect to how frequent, how intense, how long, what type, and for whom exercise should be prescribed. Investigating the biology of exercise is challenging because its effects are dynamic, multisystemic, and dependent on a myriad of endogenous and exogenous factors. Exercise is known to modulate multiple interconnected pathways, including those related to insulin and glucose metabolism, lipid metabolism, and inflammation. In the current " omic " era of research, metabolomic analyses stand as an attractive approach for systematically interrogating the effects of exercise on these pathways. Metabolite profiling of a tissue sample, such as human plasma, involves using a technology such as nuclear magnetic resonance spectroscopy or mass spectrometry to quantify prevalent small molecules, including analytes that are precursors or products of common metabolic pathways. 6 Thus, high-throughput metabolite profiling offers the opportunity to capture snapshots of biochemical activity in an individual at multiple time points over the course of engaging in physical activity. If we anticipate that metabolite profiles will differ based on the timing of exposure to physical activity, a combination of short-term and long-term studies may help to provide a complete picture of the biochemical response to exercise. In effect, we can use metabolite profiling to assess biochemical activity during or immediately after exercise (stress phase), 7 after participation in an extended exercise program (conditioning phase), 8 and in the setting of routine physical activity maintained over the longer term (conditioned phase). With respect to short-term studies, Lewis and colleagues 7 have shown that the acute response to an exercise stress …