Cerium Oxide Nanoparticles Achieve Long-Lasting Senescence Inhibition in an Aging Mouse Model of Sarcopenia via Reactive Oxygen Species Scavenging and CILP2 Downregulation.

Abstract

Most drugs used to treat sarcopenia are ineffective. Herein, the long-acting anti-sarcopenic properties of cerium oxide nanoparticles (CeNPs) and their underlying mechanisms of action are investigated in aging mice (treated with 4-hydroperoxy cyclophosphamide (4-HC)). CeNPs (size, 27.5 nm) with a fluorite crystallization structure are synthesized and subjected to X-ray diffraction and gas adsorption analyzes. Synthesized CeNPs exhibit Ce³⁺ and Ce⁴⁺ on their surfaces, a specific surface area within the standard range, and self-regenerative antioxidative functions. Synthesized CeNPs reduce reactive oxygen species (ROS) levels and exhibit good biocompatibility in muscle satellite (C2C12) cells. According to Rotarod, tensile, and histological analyzes, CeNP treatment once per week in 4-HC-treated mice markedly increases muscle strength and the cross-sectional muscle tissue area relative to that in control mice. Next-generation sequencing identifies CILP2 as a key differentially upregulated gene common to aging muscle tissues and satellite cells in the presence of ROS. Quantitative polymerase chain reaction and western blotting confirm CILP2, Serpine1, phospho-p21, Atrogin-1, and Cxcl10 downregulation in CeNP-treated mice (compared with 4-HC-treated mice); in vitro CILP2 knockdown results in Serpine1 and phospho-p21 downregulation. These findings confirm the long-acting effects of CeNPs against sarcopenia in older individuals.