High-content phenotypic analysis of a C. elegans recombinant inbred population identifies genetic and molecular regulators of lifespan

Gao, A. W.; El Alam, G. W.; Zhu, Y.; Li, W.; Katsyuba, E.; Sulc, J.; Li, T.; Li, X.; Overmyer, K. A.; Lalou, A.; Mouchiroud, L.; Bou Sleiman, M.; Cornaglia, M.; Morel, J.-D.; Houtkooper, R.; Coon, J.; Auwerx, J.

doi:10.1101/2024.01.15.575638

bioRxiv · 10.1101/2024.01.15.575638

High-content phenotypic analysis of a C. elegans recombinant inbred population identifies genetic and molecular regulators of lifespan

Gao, A. W.·El Alam, G. W.·Zhu, Y.·Li, W.·Katsyuba, E.·Sulc, J.·Li, T.·Li, X.·Overmyer, K. A.·Lalou, A.·Mouchiroud, L.·Bou Sleiman, M.·Cornaglia, M.·Morel, J.-D.·Houtkooper, R.·Coon, J.·Auwerx, J.

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Abstract

Lifespan is influenced by complex interactions between genetic and environmental factors. Studying those factors in model organisms of a single genetic background limits their translational value for humans. Here, we mapped lifespan determinants in 85 genetically diverse C. elegans recombinant intercross advanced inbred lines (RIAILs). We assessed molecular profiles - transcriptome, proteome, and lipidome - and life-history traits, including lifespan, development, growth dynamics, and reproduction. RIAILs exhibited large variations in lifespan, which positively correlated with developmental time. Among the top candidates obtained from multi-omics data integration and QTL mapping, we validated known and novel longevity modulators, including rict-1, gfm-1 and mltn-1. We translated their relevance to humans using UK Biobank data and showed that variants in RICTOR and GFM1 are associated with an elevated risk of age-related heart disease, dementia, diabetes, kidney, and liver diseases. We organized our dataset as a resource (https://lisp-lms.shinyapps.io/RIAILs/) that allows interactive explorations for new longevity targets.

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Gao, A. W., El Alam, G. W., Zhu, Y., Li, W., Katsyuba, E., Sulc, J., Li, T., Li, X., Overmyer, K. A., Lalou, A., Mouchiroud, L., Bou Sleiman, M., Cornaglia, M., Morel, J.-D., Houtkooper, R., Coon, J., Auwerx, J.. 2024-01-16. High-content phenotypic analysis of a C. elegans recombinant inbred population identifies genetic and molecular regulators of lifespan. https://doi.org/10.1101/2024.01.15.575638

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