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,
Jonathan Sulc,
Xiaoxu Li,
Elena Katsyuba,
Terytty Y. Li,
Katherine A. Overmyer,
Amelia Lalou,
Laurent Mouchiroud,
Maroun Bou Sleiman,
Matteo Cornaglia,
Jean-David Morel,
Riekelt H. Houtkooper,
Joshua J. Coon,
Johan Auwerx
Affiliations
Arwen W. Gao
Laboratory of Integrative Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology, and Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands; Corresponding author
Gaby El Alam
Laboratory of Integrative Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
Yunyun Zhu
Department of Biomolecular Chemistry, University of Wisconsin, Madison, WI 53506, USA
Weisha Li
Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology, and Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands
Jonathan Sulc
Laboratory of Integrative Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
Xiaoxu Li
Laboratory of Integrative Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
Elena Katsyuba
Laboratory of Integrative Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; Nagi Bioscience SA, EPFL Innovation Park, 1025 Saint-Sulpice, Switzerland
Terytty Y. Li
Laboratory of Integrative Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
Katherine A. Overmyer
Department of Biomolecular Chemistry, University of Wisconsin, Madison, WI 53506, USA; National Center for Quantitative Biology of Complex Systems, Madison, WI 53706, USA; Morgridge Institute for Research, Madison, WI 53515, USA
Amelia Lalou
Laboratory of Integrative Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
Laurent Mouchiroud
Laboratory of Integrative Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; Nagi Bioscience SA, EPFL Innovation Park, 1025 Saint-Sulpice, Switzerland
Maroun Bou Sleiman
Laboratory of Integrative Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
Matteo Cornaglia
Nagi Bioscience SA, EPFL Innovation Park, 1025 Saint-Sulpice, Switzerland
Jean-David Morel
Laboratory of Integrative Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
Riekelt H. Houtkooper
Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology, and Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands
Joshua J. Coon
Department of Biomolecular Chemistry, University of Wisconsin, Madison, WI 53506, USA; National Center for Quantitative Biology of Complex Systems, Madison, WI 53706, USA; Morgridge Institute for Research, Madison, WI 53515, USA; Department of Chemistry, University of Wisconsin, Madison, WI 53506, USA
Johan Auwerx
Laboratory of Integrative Systems Physiology, Interfaculty Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; Corresponding author
Summary: 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 C. elegans recombinant inbred advanced intercross 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 correlated positively with developmental time. We validated three longevity modulators, including rict-1, gfm-1, and mltn-1, among the top candidates obtained from multiomics data integration and quantitative trait locus (QTL) mapping. We translated their relevance to humans using UK Biobank data and showed that variants in GFM1 are associated with an elevated risk of age-related heart failure. We organized our dataset as a resource that allows interactive explorations for new longevity targets.
