Comparative Transcriptomics Identifies Altered Neuronal and Metabolic Function as Common Adaptations to Microgravity and Hypergravity in Caenorhabditis elegans

Human exploration of deep space is firmly within reach, but health decline during extended spaceflight remains a key challenge. To provide a novel mechanistic foundation for future targeted therapeutics, we employed the worm Caenorhabditis elegans to contrast hypergravity versus microgravity and identified reproducible molecular signatures. Using NASA’s GeneLab Repository, we performed comparative transcriptomic analysis of C. elegans responses to 5xg, 10xg and 15xg hypergravity, and to two spaceflight experiments (ICE-FIRST and CERISE). We found that: (i) progressive hypergravitational load concomitantly increases the extent of differential gene regulation; (ii) subtle changes in 1032 genes are reproducibly observed during spaceflight-induced microgravity, and; (iii) 189 genes display comparable unidirectional expression changes during both hypergravity and microgravity. Within genes concordantly regulated by altered gravity per se, we identify several candidate targets (network hubs and putative transcriptional regulators) with terrestrial roles in neuronal function and/or cellular metabolism, which are linked to regulation by daf-16/FOXO signalling. Whilst comprising a smaller subset (n = 46 genes), genes displaying inverted expression profiles during hyper- versus microgravity were involved in a metabolic reprogramming response, also under putative control of daf-16/FOXO. Thus, neuronally-mediated changes in FOXO-mediated metabolic reprogramming might represent a promising therapeutic avenue against negative health effects of altered gravity.