Understanding Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Physical Fatigue Through the Perspective of Immunosenescence

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating illness marked by persistent fatigue, yet its mechanisms remain unclear. Growing evidence implicates immunosenescence-the age-related decline in immune function-in the onset and persistence of fatigue. METHODS: This review synthesizes clinical and experimental data to examine how immunosenescence contributes to ME/CFS. We focus on chronic inflammation, senescent immune phenotypes, mitochondrial dysfunction, and neuroendocrine imbalance, with emphasis on maladaptive crosstalk among immune, muscular, neuroendocrine, and vascular systems. RESULTS: Aging immune cells drive chronic inflammation that impairs mitochondrial ATP production and promotes muscle catabolism. Concurrently, HPA-axis suppression and β₂-adrenergic dysfunction amplify immune dysregulation and energy imbalance. Together, these processes illustrate how immunosenescence sustains pathological cross-organ signaling underlying systemic fatigue. CONCLUSION: Immunosenescence provides a unifying framework linking immune, metabolic, and neuroendocrine dysfunction in ME/CFS. Recognizing cross-organ communication highlights its clinical relevance, suggesting biomarkers such as cytokines and exhaustion markers, and supports integrated therapeutic strategies targeting immune and metabolic networks.