High-content phenotypic analysis of a C. elegans recombinant inbred population identifies genetic and molecular regulators of lifespan
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.
Authors
- Johan Auwerx (ORCID: https://orcid.org/0000-0002-5065-5393)
- Katherine A. Overmyer (ORCID: https://orcid.org/0000-0002-1929-1229)
- Riekelt H. Houtkooper (ORCID: https://orcid.org/0000-0001-9961-0842)
- Amélia Lalou
- Maroun Bou Sleiman (ORCID: https://orcid.org/0000-0002-1375-7577)
- Arwen W. Gao (ORCID: https://orcid.org/0000-0001-7687-8926)
- Jean‐David Morel (ORCID: https://orcid.org/0000-0002-7122-9924)
- Laurent Mouchiroud
- Xiaoxu Li (ORCID: https://orcid.org/0000-0001-5121-9190)
- Terytty Yang Li (ORCID: https://orcid.org/0000-0003-3684-7935)
- Matteo Cornaglia
- Elena Katsyuba (ORCID: https://orcid.org/0000-0001-7399-7110)
- Gaby El Alam (ORCID: https://orcid.org/0000-0002-1396-1332)
- Jonathan Sulc (ORCID: https://orcid.org/0000-0002-5572-6541)
- Weisha Li (ORCID: https://orcid.org/0000-0002-1370-6067)
- Yunyun Zhu (ORCID: https://orcid.org/0000-0002-0087-3464)
- Joshua J. Coon (ORCID: https://orcid.org/0000-0002-0004-8253)
Institutions
- University of Wisconsin–Madison (US)
- ESI Group (Switzerland) (CH)
- École Polytechnique Fédérale de Lausanne (CH)
- University of Amsterdam (NL)
Publication Details
- Journal
- Cell Reports
- Published
- 2024-10-01
- DOI
- https://doi.org/10.1016/j.celrep.2024.114836
- Citations
- 5
- Primary Topic
- Genetics, Aging, and Longevity in Model Organisms
- Type
- article
- Field-Weighted Citation Impact
- 1.14
Funders
- National Science Foundation
- Foundation for the National Institutes of Health
- Human Frontier Science Program
- University of Wisconsin-Madison
- Velux Stiftung
- University of Wisconsin Carbone Cancer Center
- United Mitochondrial Disease Foundation
- Amsterdam University Medical Centers
- National Research Foundation
- École Polytechnique Fédérale de Lausanne
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- National Research Foundation of Korea
- China Scholarship Council
- National Institutes of Health
- HORIZON EUROPE Marie Sklodowska-Curie Actions
- HORIZON EUROPE European Research Council