Exercise–nutrition–myokine–mitochondrial interactions in immune aging: an immunometabolic framework for host defense

Exercise is increasingly recognized as a systemic modulator of immune and metabolic physiology, with potential relevance to immune aging, chronic low-grade inflammation, and host defense. This structured narrative review integrates evidence on the interplay among exercise, skeletal-muscle-derived signaling, mitochondrial adaptation, and nutritional context to develop a conceptual framework for immunometabolic reprogramming during immune aging. Literature was identified through searches of PubMed/MEDLINE, Web of Science, Scopus, and Google Scholar using combinations of terms related to exercise, myokines/exerkines, mitochondria, nutrition, immunosenescence, inflammaging, and host defense. We synthesize evidence across human, animal, and cellular studies, while distinguishing direct human findings from associative and preclinical mechanistic evidence. Particular attention is given to exercise-induced myokine signaling, mitochondrial biogenesis and function, metabolic flexibility, redox signaling, and mitochondrial quality control, as well as the potential modifying effects of macronutrients, amino acids, fatty acids, micronutrients, and dietary bioactive compounds. The review further considers how exercise and nutritional context may influence features of immunosenescence and inflammaging and examines their potential relevance to vaccine responses and infection-related host defense. Importantly, changes in circulating biomarkers or immune-cell phenotypes are not assumed to represent improved immune competence or clinical protection. Instead, the available evidence is interpreted according to exercise modality and dose, training status, age, sex, nutritional and metabolic context, and the level of biological evidence. Overall, this framework highlights the potential for exercise–nutrition interactions to shape immune–metabolic communication while emphasizing that several proposed myokine–mitochondrial–immune links remain associative or mechanistic hypotheses requiring prospective human investigation.