Aberrant 5-Methylcytosine tRNA Modification Disrupts Proteostasis and Exacerbates Age-Related Osteoporosis

Age-related protein aggregation drives senile osteoporosis. Aberrant tRNA modifications exacerbate the progression, yet mechanisms linking these to bone loss remain unclear. In this study, we identify Nsun2 (m5C methyltransferase) as key regulator: age-dependent Nsun2 downregulation in BMSCs reduces mC levels of tRNAs, destabilizing tRNAs and impairing translation efficiency of specific transcripts. This directly disrupts the protein synthesis of molecular chaperone and pro-osteogenic factors, accelerating misfolded protein aggregates and activating unfolded protein response, inducing BMSCs senescence and impairing osteogenesis. Mice specifically depleted of Nsun2 exhibited reduced bone mass, whereas mice overexpressing Nsun2 alleviated age-associated bone loss. Notably, the exacerbated protein aggregation and bone mass loss in Nsun2-deficient mice were ameliorated following treatment with the molecular chaperone activator-ML346. Remarkably, ML346 administration proved sufficient to reverse age-related functional deficits in aged mice. Overall, our findings demonstrate that aberrant tRNA-m5C modification alters protein synthesis and induces proteostasis collapse, which constitute a novel contributor to the pathogenesis of senile osteoporosis. Additionally, reduction of protein aggregation through the activation of molecular chaperones presents a promising therapeutic strategy for this disease.