Niclosamide extends health span and reduces frailty by ameliorating mTORC1 hyperactivation in aging models.

Abstract

INTRODUCTION: Frailty is characterized by an increased vulnerability to disease and physical debilitation due to a decline in the body's capacity to maintain homeostasis during aging. Therefore, effective management of frailty is crucial for promoting health. Although the role of niclosamide (NIC), an autophagy promoter, has been studied for the treatment of cancer, infectious diseases, and metabolic disorders, no research has focused on its effects on aging. OBJECTIVES: In this study, we aimed to evaluate the effects of NIC on the aging process and assess its potential as a novel anti-aging therapeutic agent. METHODS: We evaluated the effects of NIC on frailty, physical function, and metabolic function using Caenorhabditis elegans (C. elegans) and aging mouse models. NIC effectiveness was assessed using behavioral experiments, histological analysis, and molecular biological analysis. RESULTS: We identified NIC as a compound that enhanced exercise capacity and metabolism, thereby alleviating frailty. Briefly, NIC extended the lifespan and improved frailty-related phenotypes in C. elegans, and effectively ameliorated frailty in aging mice, particularly in muscle aging. Additionally, NIC treatment suppressed the muscle atrophy-related ubiquitin-proteasome system induced by mammalian target of rapamycin complex 1 (mTORC1) hyperactivation, while enhancing autophagic flux, another aspect of proteostasis. Furthermore, mRNA-seq analysis revealed that NIC improved metabolism-related functions. CONCLUSION: Collectively, these findings suggest that NIC is a promising novel candidate for the prevention of frailty.