High-content Phenotypic Analysis of Recombinant Inbred Population Identifies Genetic and Molecular Regulators of Lifespan

Overview

Journal bioRxiv

Date 2024 Jan 31

PMID 38293129

Authors

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

Affiliations

Soon will be listed here.

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 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 , and . We translated their relevance to humans using UK Biobank data and showed that variants in and 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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