The average age of the population is increasing worldwide, which has a profound impact on our society. This leads to an increasing demand for medicines and requires the development of new strategies to promote health during the additional years. In the search for resources and therapeutics for improved health during an extended life span, attention has to be paid to environmental exposure and ecosystem burdens that inevitably emerge with the extended consumption of medicines and drug development, even in the preclinical stage. The hereby introduced sustainable strategy for drug discovery is built on 3Rs, “Robustness, Reliability, and saving Resources”, inspired by both the 3Rs used in animal experiments and environmental protection, and centers on the usefulness and the variety of the small model organism Caenorhabditis elegans for detecting health-promoting natural products. A workflow encompassing a multilevel screening approach is presented to
maximize the amount of information on health-promoting samples, while considering the 3Rs. A detailed, methodology- and praxis-oriented compilation and discussion of proposed C. elegans health span assays and more disease-specific assays are presented to offer guidance for scientists intending to work with C. elegans, thus facilitating the initial steps towards the integration of C. elegans assays in their laboratories.