Exercise as Medicine: The Potential of Exerkines as Therapeutics

Exercise delivers a wide variety of health benefits through many mechanisms, including the release of exerkines, signaling molecules secreted by multiple tissues during physical activity. We evaluated 34 exerkines with therapeutic potential alongside IC7Fc (an engineered IL-6/CNTF derivative), classifying them based on (a) their translational readiness as therapeutics and (b) their primary clinical domains (cardiovascular, metabolic, neurological, musculoskeletal, anti-inflammatory, and oncology). Only four have clear clinical validation, and nine others have reached clinical testing or late preclinical development. Across these molecular entities, three challenges emerge: context-dependent effects, drug-delivery constraints, and network dynamics. We conclude with an assessment of opportunities and strategies for the creation of exerkine-based biomarkers and for using exerkines to facilitate therapeutic discovery. Finally, we present the Exerkine Atlas (https://exerkineatlas.org/), an open-access web resource integrating curated literature and clinical trial data for all 35 molecules.