Abstract

Microbial communities profoundly influence host aging, yet how natural genetic variation determines microbiota-driven longevity remains unclear. By screening root-derived bacterial isolates across genetically diverse Caenorhabditis elegans strains, we identified striking phenotypic heterogeneity, ranging from lifespan extension to accelerated aging. Combining classical genetic analysis, quantitative trait locus (QTL) mapping and CRISPR-Cas9 allelic recapitulation, we identify skn-1 (Nrf2) and gsy-1 (glycogen synthase) as key host determinants. We demonstrate that strains with mutations or specific natural variants in these loci exhibit a compromised redox buffering capacity, leading to systemic oxidative stress, loss of tissue integrity, and premature death upon microbial challenge. Conversely, robust hosts utilize the same microbial signals to promote longevity. Notably, lifespan defects in susceptible individuals were rescued by antioxidant supplementation. These findings establish redox homeostasis as a central axis in host-microbe-aging interactions and provide a mechanistic framework for precision microbiome interventions tailored to host genetic backgrounds.