Genetic basis of enhanced stress resistance in long-lived mutants highlights key role of innate immunity in determining longevity

Mutations that extend lifespan are associated with enhanced resistance to stress. To better understand the molecular mechanisms underlying this relationship, we studied nine long-lived C. elegans mutants representative of different pathways of lifespan extension. We directly compared the magnitude of their lifespan extension and their ability to resist various external stressors (heat, oxidative stress, bacterial pathogens, osmotic stress, and anoxia). Furthermore, we analysed gene expression in each of these mutants to identify genes and pathways responsible for the enhanced resistance to stress. All of the examined long-lived mutants have increased resistance to one or more type of stress. Resistance to each of the examined types of stress had a significant, positive correlation with lifespan, with bacterial pathogen resistance showing the strongest relationship. All of the examined long-lived mutants have significant upregulation of multiple stress response pathways but differ in which stress response pathway has the greatest enrichment of genes. We used RNA sequencing data to identify which genes are most highly correlated with each type of stress resistance. There was a highly significant overlap between genes highly correlated with stress resistance, and genes highly correlated with longevity, suggesting that the same genetic pathways drive both phenotypes. This was especially true for genes correlated with bacterial pathogen resistance, which showed an 84% overlap with genes correlated with lifespan. Overall, our results demonstrate a strong correlation between stress resistance and longevity that results from the high degree of overlap in genes contributing to each phenotype.