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

Area of Science:

• Gerontology and Muscle Biology
• Drug Discovery and Development

Background:

• Sarcopenia, a key aspect of musculoskeletal aging, lacks approved therapies, hindering effective treatment development.
• Identifying promising sarcopenia interventions is difficult due to the vast diversity of potential candidates and the limitations of aged-mammal models for initial screening.

Purpose of the Study:

• To propose and describe a C. elegans-to-mouse discovery framework for accelerating the development of sarcopenia interventions.
• To outline a strategy for efficient early-stage prioritization of therapeutic candidates for skeletal muscle aging.

Main Methods:

• Utilizing Caenorhabditis elegans (C. elegans) for rapid, organism-level assessment of locomotor function, muscle integrity, and conserved aging mechanisms.
• Screening diverse candidate interventions, including natural products and compounds, in C. elegans to prioritize candidates for further validation in aged-mammal models.
• Integrating function-centered screening with conserved biological mechanisms (e.g., mitochondrial quality control, proteostasis) for cross-species interpretation.

Main Results:

• The C. elegans model allows for efficient screening of large candidate pools, including various compounds, doses, and combinations.
• Preservation of age-related function in C. elegans serves as a primary criterion for selecting interventions.
• Examples like urolithin A, norharmane, and spermidine demonstrate successful integration of worm-based screening with mechanistic data and mouse validation.

Conclusions:

• A C. elegans-to-mouse framework enhances the prioritization of sarcopenia interventions by combining functional screening with mechanistic insights.
• This approach accelerates the discovery of function-preserving therapeutics for age-related skeletal muscle decline.
• The proposed framework offers a practical strategy to overcome challenges in sarcopenia intervention development.