Using Automated Monitoring Technology to Advance C. elegans as a Model in Ageing and Neurodegenerative Disease Drug Discovery

Abstract

Targeting the underlying process of ageing using pharmacological interventions may prevent chronic disease development and extend the period of healthy living. The use of automated monitoring technology (AMT) for the short-lived model organism Caenorhabditis elegans may improve drug success rates by allowing for earlier in vivo results to be collected on which compounds may improve health. This work finds that the automated monitoring of worm movement over 7 days instead of across its entire lifespan is sufficient to identify health improvements associated with lifespan extensions. This rapid evaluation of ageing interventions allows higher throughput screening compared to previous manual methods, and improves robustness and reproducibility which is required for industrial drug discovery. Several interventions reported to increase lifespan were tested on this system such as rapamycin, metformin, and alpha-ketoglutarate (aKG). However, only sulfamethoxazole and aKG were found to reliably improve movement in 7 days, suggesting that method standardisation across the literature may stand as one of the major barriers to the use of C. elegans in the drug discovery pipeline.
Drugs against ageing may be especially beneficial to neurodegenerative diseases (NDs) which have few therapies and are strongly age-associated. Constant monitoring of movement and speed revealed previously unseen behavioural differences dependent on the aggregating protein and tissue of expression in C. elegans models of ND. When these models were exposed to compounds which hadsuccessfully improved movement in the control strain, it was found that the ageing interventions had did not necessarily have positive effects on ND model movement. This lack of effect was not due to the method of sterility which was examined as a potential cause for the difference in results. This work presents novel evidence on the efficacy of ageing interventions in C. elegans and how they are measured, as well as novel movement phenotypes of ND models, and the impact of methodological differences in drug screening while also evaluating a novel AMT; the WormGazer.