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

Arwen W Gao; Gaby El Alam; Yunyun Zhu; Weisha Li; Elena Katsyuba; Jonathan Sulc; Terytty Y Li; Xiaoxu Li; Katherine A Overmyer; Amelia Lalou; Laurent Mouchiroud; Maroun Bou Sleiman; Matteo Cornaglia; Jean-David Morel; Riekelt H Houtkooper; Joshua J Coon; Johan Auwerx

doi:10.1101/2024.01.15.575638

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

bioRxiv [Preprint]. 2024 Jan 16:2024.01.15.575638. doi: 10.1101/2024.01.15.575638.

Authors

Arwen W Gao^{1

2}, Gaby El Alam¹, Yunyun Zhu³, Weisha Li², Elena Katsyuba^{1

4}, Jonathan Sulc¹, Terytty Y Li^{1

5}, Xiaoxu Li¹, Katherine A Overmyer^{3

6

7}, Amelia Lalou¹, Laurent Mouchiroud^{1

4}, Maroun Bou Sleiman¹, Matteo Cornaglia⁴, Jean-David Morel¹, Riekelt H Houtkooper², Joshua J Coon^{3

6

7

8}, Johan Auwerx¹

Affiliations

¹ Laboratory of Integrative Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
² Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology, and Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
³ Department of Biomolecular Chemistry, University of Wisconsin, Madison, WI 53506, USA.
⁴ Nagi Bioscience SA, EPFL Innovation Park, CH-1025 Saint-Sulpice, Switzerland.
⁵ Present address: State Key Laboratory of Genetic Engineering, Shanghai Key Laboratory of Metabolic Remodeling and Health, Laboratory of Longevity and Metabolic Adaptations, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China.
⁶ National Center for Quantitative Biology of Complex Systems, Madison, WI 53706, USA.
⁷ Morgridge Institute for Research, Madison, WI 53515, USA.
⁸ Department of Chemistry, University of Wisconsin, Madison, WI 53506, USA.

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.

Keywords: C. elegans; QTL mapping; UK Biobank; genetic reference populations; gfm-1/GFM1; life-history traits; longevity; multi-omics; rict-1/RICTOR; systems genetics.

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