Genetic mapping of lifespan and mitochondrial stress response in C. elegans

Li, X., Li, W., Gao, A. W., Zhu, Y., Katsyuba, E., Overmyer, K. A., Li, T., Wang, Z., Legon, L., Plantade, L., Mouchiroud, L., Cornaglia, M., Li, H., Houtkooper, R., Auwerx, J.

Laboratory of Integrative Systems Physiology, Ecole Polytechnique Federale de Lausanne · biorxiv

Paper

Abstract

The mitochondrial unfolded protein response (UPRmt) is one of the mito-nuclear regulatory circuits that restores mitochondrial function upon stress conditions, promoting metabolic health and longevity. However, the complex gene interactions that govern this pathway and its role in aging and healthspan remain to be fully elucidated. Here, we activated the UPRmt using doxycycline (Dox) in a genetically diverse C. elegans population comprising 85 strains and observed large variation in Dox-induced lifespan extension across these strains. Through multi-omic data integration, we identified an aging-related molecular signature that was partially reversed by Dox. To identify the mechanisms underlying Dox-induced lifespan extension, we applied quantitative trait locus (QTL) mapping analyses and found one UPRmt modulator, fipp-1/FIP1L1, which was functionally validated in C. elegans and humans. In the human UK Biobank, FIP1L1 was associated with metabolic homeostasis, underscoring its translational relevance. Overall, our findings demonstrate a novel UPRmt modulator across species and provide insights into potential translational research.

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Research summary

The paper identifies a UPRmt modulator, fipp-1/FIP1L1, that influences lifespan extension in C. elegans and has translational relevance in humans. The research explores mechanisms of aging and potential interventions that could impact longevity.

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