A C. elegans-to-Mouse Discovery Framework for Prioritizing Sarcopenia Interventions.

Sarcopenia is a manifestation of musculoskeletal aging, yet no approved therapy is available. A major challenge is not the lack of potential interventions, but the difficulty of efficiently identifying which candidates should advance to aged-mammal validation.

Sarcopenia is driven by multiple biological processes, including mitochondrial dysfunction, impaired proteostasis, redox dysregulation, inflammaging, and altered nutrient sensing. Consequently, candidate interventions encompass not only conventional drug candidates but also natural products, dietary compounds, food-derived metabolites, and multi-component formulations.

This diversity creates a candidate space that is difficult to systematically evaluate using aged-mouse models alone. Here, we propose a C.

elegans-to-mouse discovery framework for sarcopenia intervention development. C.

elegans enables rapid organism-level assessment of locomotor function, muscle integrity, toxicity, genetic dependency, and conserved aging mechanisms within a single in vivo system. These features allow large candidate pools, including diverse compounds, doses, and combinations, to be screened and prioritized before resource-intensive mammalian studies.

Within this framework, preservation of age-related function serves as the primary selection criterion, whereas conserved biological mechanisms provide additional support for candidate advancement. Mitochondrial quality control, redox resilience, proteostasis, and gut-muscle communication are discussed as representative domains that facilitate cross-species interpretation.

Examples including urolithin A, norharmane, and spermidine illustrate how worm-based functional screening can be integrated with mechanistic evidence and aged-mouse validation. Collectively, this review proposes a practical framework that integrates function-centered screening with conserved mechanistic interpretation to improve early-stage prioritization of sarcopenia interventions.

This framework provides a conceptual strategy for accelerating the discovery of function-preserving therapeutics for skeletal muscle aging.