Amino Acid Metabolic Flexibility: A Framework for Locating Anabolic Resistance in Aging and Obesity-Related Insulin Resistance

Anabolic resistance, a reduced muscle protein synthetic response to protein or exercise, is reported in older adults and in people with obesity and insulin resistance. Yet it is still measured with one readout: the increment in muscle protein synthesis over a few hours after a single dose. This review makes four contributions. First, it identifies five impasses: single doses confound sensitivity with maximal responsiveness; most of an ingested meal goes untracked; breakdown is rarely measured; individual reproducibility is unknown; and acute responses are not validated predictors of muscle mass. Second, it proposes amino acid metabolic flexibility as a disposal framework in which an attenuated response can arise through four routes: reduced delivery, impaired sensing and translation, competing oxidative disposal, and impaired antiproteolysis. Third, it treats exercise as a probe as well as a stimulus, because whether prior exercise corrects a deficit helps to locate it. Fourth, applying the framework to aging and obesity-related insulin resistance suggests that similar synthetic phenotypes arise through different routes and yields a testable hypothesis: that insulin resistance diverts absorbed amino acids toward oxidation. A multidomain, repeated-measures design to test these predictions is outlined.