The cost of reproduction, i.e. a decreased lifespan due to reproduction, is a crucial trade-off which drives life-history evolution in nearly all species, including humans. A key question in evolutionary and aging research is how this trade-off is regulated in natural populations. Although some induced mutations affecting lifespan also alter the reproductive state, detailed knowledge about the genetic control of the trade-off between lifespan and offspring in natural populations is scant. We combined life-history analysis and mapping of global gene transcription profiles in a C. elegans population of recombinant inbred lines (RILs) obtained from a cross between wildtypes N2 and CB4856. We found a trade-off between lifespan and offspring across the RILs and detected 27 gene transcripts that were highly correlated to both traits in an opposite way. These genes had 20% more eQTLs, i.e. were more regulated, than the less correlated genes. Using a candidate gene approach we show that knocking-down one of these genes, the autophagy gene
unc-51, with RNAi increased offspring with 30% while decreasing lifespan with 15%. By introgressing a trans-acting CB4856 locus into N2 we show that the RNAi effect on the trade-off was modulated. Together our results demonstrate that the trade-off between lifespan and offspring can be highly regulated early in life and suggest that natural variation can tune C. elegans life-history by regulating
unc-51 transcription during the L3 stage. Interestingly, the results also indicate that RNAi phenotypes depend strongly on the genetic background due to epistatic interactions and trans-acting loci.