Host Oxidative Response Capacity Determines Longevity Outcomes of Microbial Interventions

TL;DR

Host genetic differences determine whether microbes extend or shorten lifespan by affecting redox balance, offering new ways to tailor microbiome interventions for longevity.

Contribution

Identifies skn-1 and gsy-1 as key genes linking host redox homeostasis to microbiota-driven aging outcomes.

Findings

Strains with compromised redox buffering show accelerated aging when exposed to microbes.

Antioxidant supplementation rescues lifespan defects in susceptible individuals.

Robust hosts use microbial signals to promote longevity through redox homeostasis.

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.

Genetic variation determines whether microbial interactions extend or shorten host lifespan via redox homeostasis. This discovery highlights the critical role of host genetics in shaping microbiota‐driven aging, offering a new framework for precision microbiome interventions tailored to individual needs for promoting longevity.

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