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

Cell Reports (Oct 2024)

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

Journal volume & issue: Vol. 43, no. 10
p. 114836

Abstract

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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.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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