An imbalance between energy uptake and energy expenditure can lead to obesity and increase the risk of coronary heart disease, high blood pressure, stroke, type II diabetes and some cancers. Given that key elements of energy pathway are evolutionary conserved, invertebrate research is an attractive alternative that overcomes the many legislative, financial and experimental hurdles typical of research with higher metazoan animals. The nematode Caenorhabditis elegans is a premier invertebrate model and has been utilized to study a wide range of topics of biomedical research including obesity, aging, toxicology, pharmaceutical and drug delivery approaches. Previous studies have suggested that raw extracts from a South African succulent (Hoodia gordonii) and P57 (the main active compound of the extracts) may exert an appetite suppressant effect. To investigate this notion in more detail, this present study aimed to pinpoint phenotypic, genetic and genomic-level responses of C. elegans treated with H. gordonii extract. Supplementing the bacterial food source with H. gordonii extract resulted in a significant reduction in growth parameters and the pharyngeal pumping rate as well as the fecundity. Likewise, it diminished the overall level of Nile Red positive compartments, which is indicative of a change in lipid metabolism. Comprehensive transcriptomics revealed that several genes involved in aging, lipid transport and reproduction were modulated following the exposure to the crude extract and pure P57. Based on these results, selected deletion mutants were studied in more detail, including fat-5 (a member of the Δ9 desaturases) and cyp-35A2 (a member of the cytochrome P450 family). The creation of a fat-5(tm420);cyp-35A2(gk317) mutant uncovered that the deletion of both genes resulted in a strain which is marked by a reduced fat content and an extended lifespan. Taken together, the results suggest the presence of a putative correlation between longevity and dietary restriction and given that both genes have human homologs, this finding may offer a new lead to investigate in higher organisms.