Serum factors mediate changes in mitochondrial bioenergetics associated with diet and exercise interventions

Mitochondrial improvements resulting from behavioral interventions, such as diet and exercise, are systemic and apparent across multiple tissues. Here, we test the hypothesis that factors present in serum, and therefore circulating throughout the body, can mediate changes in mitochondrial function in response to intervention. To investigate this, we used stored serum from a clinical trial comparing resistance training (RT) and RT plus caloric restriction (RT + CR) to examine effects of blood borne circulating factors on myoblasts in vitro. We report that exposure to dilute serum is sufficient to mediate bioenergetic benefits of these interventions. Additionally, serum-mediated bioenergetic changes can differentiate between interventions, recapitulate sex differences in bioenergetic responses, and is linked to improvements in physical function and inflammation. Using metabolomics, we identified circulating factors associated with changes in mitochondrial bioenergetics and the effects of interventions. This study provides new evidence that circulating factors play a role in the beneficial effects of interventions that improve healthspan among older adults. Understanding the factors that drive improvements in mitochondrial function is a key step towards predicting intervention outcomes and developing strategies to countermand systemic age-related bioenergetic decline.