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

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, highlighting its translational relevance. Overall, our dataset (https://lisp-lms.shinyapps.io/RIAILs_Dox/) serves as a unique resource to dissect lifespan and mitochondrial stress response modulators in a large genetic reference population.