Uncovering signatures of exerkines that mediate cognitive function in aging

Exercise alleviates age-related cognitive impairment, but the mechanisms underlying its benefits and how they directly affect cognitive function remain poorly characterized. One potential mechanism involves exerkines, which are signaling molecules (e.g., proteins, metabolites) released from tissues during exercise. Some exerkines are produced within the brain and act locally through paracrine signaling, whereas others originate in peripheral tissues and modulate brain function through endocrine pathways. Preliminary data from 6-month-old mice exercised on running wheels indicate that skeletal muscle-derived exerkines (and related genes) positively correlate with biological pathway scores related to neurogenesis and cognition in the hippocampus. Despite emerging evidence linking exerkines to brain function, a comprehensive analysis of exerkine expression across peripheral tissues (e.g., skeletal muscle, adipose) and the brain (e.g., hippocampus), as well their relationship to cognitive function, has yet to be investigated. We hypothesize that exerkine expression, from peripheral tissues and within the brain, are strongly associated exercise-related improvements in cognitive function. Here, we exercised young (2-month) and old (18-month) mice on voluntary running wheels for six weeks and assessed cognitive function (e.g., elevated plus maze, Morris water maze) alongside physiological responses to exercise training (e.g., aerobic capacity, body composition). Exercise restored anxiety-like behavior and showed a trend towards improving spatial memory in old mice. Although exercise did not increase relative VO2max in old mice, exercised mice required more time to reach VO2max, resulting in greater distance travelled and more work performed, indicating evidence of improved exercise capacity. Lastly, body composition analysis revealed trends of reduced body fat and increased lean mass in older exercised mice. To identify exerkines associated with cognitive function and aerobic capacity, we are currently performing RNA-seq combined with network analyses to profile gene signaling and in parallel measuring neurogenesis (through EdU labeling), exercise-responsive signaling pathways (e.g., AMPK, BDNF), and hallmarks of aging (e.g., neuroinflammation, mitochondrial dysfunction, senescence). In summary, voluntary wheel running improves behavioral and cognitive function, enhances exercise capacity, and may positively affect body composition in old mice, with these effects potentially mediated by exerkines. This work was supported by funding from the National Institute of Neurological Disorders and Stroke (T32NS07222) and the Frank L. and Helen Gofrank Foundation. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.