Exercise mimetics: molecular mechanisms, biological and therapeutic effects

Accumulating evidence underscores the therapeutic benefits of exercise in the prevention and treatment of various diseases. However, many patients are unable to engage in sufficient physical training because of frailty, disability, or disease burden. This challenge has stimulated considerable interest in exercise mimetics, which are pharmacological or biological interventions designed to activate exercise-responsive pathways and recapitulate the key adaptive responses elicited by physical activity. In this Review, we outline the conceptual foundations, classification, historical evolution, and biological rationale of exercise mimetics, and organize the field according to its major mechanisms, including neurotrophic signaling, redox regulation, immune modulation, mechanotransduction, vascular coupling, mitochondrial metabolism, epigenetic remodeling, and inter-organ crosstalk. We further examine how these pathways shape normal physiology and development, with an emphasis on metabolic homeostasis, neurodevelopment, cognition, aging, angiogenesis, and inflammation. Building on this framework, we evaluate emerging applications in major human diseases, including cancer, traumatic injury, cardiovascular disorders, neurodegenerative disorders, and inflammatory or immune-mediated conditions, with particular attention to neuroregeneration and systems-level repair. Finally, we assess clinical and translational advances in biomarker-guided diagnosis, personalized treatment, circulating mediators, drug delivery, combination therapy, and clinical trials. Although exercise mimetics offer a scalable and mechanism-informed therapeutic strategy, most evidence to date remains preclinical, and substantial challenges related to pharmacokinetics, safety, target engagement, and patient heterogeneity must be overcome before clinical implementation.