Stress tolerance and lifespan in C. elegans are modulated by natural allelic variation in cmk-1

Genetic control of aging in C. elegans has primarily been studied using derived mutants of the strain N2. These mutants often display extreme lifespan accompanied by increased stress resistance. Yet, identification of genes that underlie variation in lifespan and stress tolerance in natural populations remains a major challenge. We investigated gene expression architecture and longevity and found that stress tolerance and lifespan in C. elegans are modulated by natural allelic variation in cmk-1. Variation in gene expression levels was linked to genomic loci (eQTL) using fully sequenced recombinant inbred populations derived from divergent wild-type strains N2 and CB4856. In these strains regulatory loci were identified under standard and under heat-stress conditions. After verification, the causal regulator was identified by screening knock-out mutants of candidate genes. Moreover, lifespan was measured under standard conditions and in strains that received a heat shock treatment. We identified a major stress-related regulatory locus that affects expression variation in more than 100 genes and one of the causal genes was found to be cmk-1. The effects of this variation include modulation of insulin-like signaling targets supporting a model in which allelic variation in cmk-1 regulates a subset of daf-16 targets under stress conditions, leading to increased stress resistance and prolonged lifespan. In conclusion, genes affecting lifespan variation in nature may not be those identified by mutagenizing a single C. elegans strain. Our data suggests that pathways previously associated with aging are affected, but not by the usual suspects.