Anti-Aging Effects of Nitazoxanide in Caenorhabditis elegans and D-Galactose-Induced Accelerated Aging Mice

Aging is a multifactorial biological process that leads to the gradual decline of physiological functions, contributing to the onset of age-related diseases. Nitazoxanide (NTZ) is an FDA-approved antiparasitic drug with anti-senescence(definition) effects. However, its anti-aging effects and the underlying molecular mechanisms remain incompletely understood. This study investigated the anti-aging effects of NTZ in Caenorhabditis elegans and in a D-galactose (D-Gal)-induced accelerated aging mouse model. In C. elegans, NTZ treatment significantly extended both lifespan and healthspan(definition), as demonstrated by reduced lipofuscin accumulation, decreased reactive oxygen species (ROS) levels, and improved locomotor activity. In the D-Gal mouse model, NTZ treatment ameliorated cognitive and physical decline, improved skin tissue integrity, and protected hippocampal neurons from degeneration. Computational target prediction and pathway analysis identified 122 potential anti-aging targets of NTZ. Network pharmacology analysis revealed that NTZ targets the PI3K signaling pathway, a key regulator of aging, and identifies PI3K p110 catalytic isoform as a central hub in this cascade, confirming its pivotal role in NTZ-mediated anti-aging effects. Molecular docking and dynamics simulations further validated the stable binding of NTZ to PI3K p110 catalytic isoforms, demonstrating a high-affinity interaction that disrupts PI3K signaling. Together, these findings provide molecular evidence supporting NTZ as a promising candidate for anti-aging therapy, with potential applications in age-related diseases.