Fibronectin type-III domain-containing protein 5 in aging-associated metabolic cardiovascular disease: From mechanism to therapy

As global aging accelerates, senescence has become one of the dominant determinants of human health. Over the past decade, fibronectin type-III domain-containing protein 5 (FNDC5), a transmembrane glycoprotein, has attracted attention because of its links to the aging process. Cleavage of FNDC5 releases the myokine irisin, which modulates glucose and lipid metabolism, drives browning of white adipocytes, and participates in cardiovascular homeostasis. This narrative review was based on searches of PubMed, Web of Science, and Scopus for records published between January 2002 and March 2026, combining the terms FNDC5 and irisin with aging, cardiometabolic disease, hypertension, atherosclerosis, cardiomyopathy, and myocardial remodeling; primary experimental studies, genetic analyses, and clinical investigations addressing FNDC5/irisin in aging or cardiometabolic disease were retained. Two features distinguish this review from earlier surveys of FNDC5/irisin. First, evidence obtained in aging models and older human populations is reported separately from evidence obtained in metabolic or cardiovascular models without an aging component, so that the aging-specific evidence base is visible throughout. Second, each disease section is organized around the level of evidence available, distinguishing mechanistic findings in cells and animals from association data in patients. On this basis, FNDC5/irisin signaling converges on the AMP-activated protein kinase/Sirtuin 1/peroxisome proliferator-activated receptor gamma coactivator 1-alpha axis, nuclear factor kappa B-and Smad3-dependent transcription, autophagic flux, and mitochondrial quality, and these nodes recur across hypertension, atherosclerosis, cardiometabolic cardiomyopathy, and myocardial remodeling. Human data are predominantly observational and define associations between circulating irisin and disease severity or outcome. Priorities for the field are receptor-level definition of irisin signaling, assay standardization, and prospective clinical studies in older populations.