Exercise as medicine The potential of exerkines as therapeutics
When we exercise, many tissues in our body release chemical messengers called exerkines. These molecules help explain why physical activity protects against heart disease, diabetes, dementia and other chronic conditions. Scientists are now investigating whether exerkines could become medicines for people unable to exercise due to disability, frailty or illness.
David Jimenez-Morales, Vidal M. Arroyo, Katryn I. Ashley, Russ B. Altman and Euan A. Ashley. Exercise as Medicine: The Potential of Exerkines as Therapeutics. Annual Review of Pharmacology and Toxicology 67 (2027). In press. DOI: 10.1146/annurev-pharmtox-060325-031237 Full citation and BibTeX →
Publication and trial counts: PubMed and ClinicalTrials.gov, snapshot of February 2026.
Exerkines by therapeutic domain and translational tier
Each exerkine has one primary therapeutic domain (columns) and one tier of translational readiness (rows). Most exerkines act on several organ systems; the primary domain is the one with the strongest evidence.
Hover over a domain to highlight its exerkines, or select an exerkine to open its profile. A superscript t marks a therapeutic target for inhibition. SeP is an inverse exerkine: its levels fall with exercise.
Tiers of translational readiness
The four tiers describe how close each exerkine is to clinical use. Approved therapies that target IL-6 and VEGF inhibit these pathways instead of supplementing them. An exerkine that is beneficial when released briefly during exercise may have weaker, stronger or even harmful effects when its levels stay high.
Clinically validated
Signaling pathways already targeted by approved drugs or established clinical protocols.
Clinical trials or advanced preclinical
Human trial data or highly developed therapeutic formulations.
Strong preclinical evidence
Strong animal-model data, identified molecular targets and defined mechanisms of action.
Emerging evidence
Preliminary promise that requires further validation, including molecules whose status as a true exerkine is still debated.
Therapeutic domains
The six domains and the conditions they include.
Heart failure, myocardial infarction, hypertension and atherosclerosis.
6 exerkines with this primary domain → Metabolic and endocrineObesity, type 2 diabetes, metabolic syndrome and nonalcoholic fatty liver disease.
8 exerkines with this primary domain → Neurological and cognitiveAlzheimer’s disease, Parkinson’s disease, depression and stroke.
8 exerkines with this primary domain → MusculoskeletalSarcopenia, muscular dystrophy, osteoarthritis and bone metabolism.
5 exerkines with this primary domain → Anti-inflammatory and immunomodulatoryAutoimmune diseases, fibrosis and sepsis.
4 exerkines with this primary domain → OncologyTumor suppression, antiangiogenesis and cancer-associated cachexia.
4 exerkines with this primary domain →Exerkines as biomarkers
Some exerkines may reach clinical use first as diagnostic or prognostic biomarkers. Klotho and GDF15 are being studied both as biomarkers and as therapeutics. Exerkines with documented biomarker applications:
Prognostic marker in cancer, cardiovascular disease and metabolic disease; chronic elevation associated with poor outcomes
SePBiomarker for metabolic disorders and insulin resistance
PF4Decreased serum levels correlate with cognitive decline in Alzheimer’s disease
OmentinInversely related to inflammatory biomarkers in heart failure with preserved ejection fraction
MyonectinDecreased circulating levels in type 2 diabetes, obesity and metabolic syndrome
Cathepsin BElevated levels predict severity of preeclampsia
ClusterinPolymorphisms and plasma levels associated with multiple sclerosis susceptibility and progression
KlothoEarly and sensitive marker of kidney function decline, starting at chronic kidney disease stage 2
Exercise activates at least 34 identified exerkines, released by at least five tissues and acting across six therapeutic domains. No single molecule can reproduce this, so an exercise pill is unlikely to replace physical activity. Individual exerkines may still reproduce specific benefits of exercise in patients who cannot be active.