SummaryThree distinct RNA polymerases (Pols) transcribe different classes of genes in the eukaryotic nucleus1. Pol III is the essential, evolutionarily conserved enzyme that generates short, non-coding RNAs, including transfer RNAs (tRNAs) and 5S ribosomal RNA (rRNA)2. Historical focus on transcription of protein-coding genes has left the roles of Pol III in organismal physiology relatively unexplored. The prominent regulator of Pol III activity, Target of Rapamycin kinase Complex 1 (TORC1), is an important longevity determinant3, raising the question of Pol III’s involvement in ageing. Here we show that Pol III limits lifespan downstream of TORC1. We find that a reduction in Pol III extends chronological lifespan in yeast and organismal lifespan in worms and flies. Inhibiting Pol III activity in the adult worm or fly gut is sufficient to extend lifespan, and in flies, longevity can be achieved by Pol III inhibition specifically in the intestinal stem cells (ISCs). The longevity phenotype is associated with amelioration of age-related gut pathology and functional decline, dampened protein synthesis and increased tolerance of proteostatic stress. Importantly, Pol III acts downstream of TORC1 for lifespan and limiting Pol III activity in the adult gut achieves the full longevity benefit of systemic TORC1 inhibition. Hence, Pol III is a pivotal output of this key nutrient signalling network for longevity; Pol III’s growth-promoting, anabolic activity mediates the acceleration of ageing by TORC1. The evolutionary conservation of Pol III affirms its potential as a therapeutic target.
BackgroundDetermining how complex traits are genetically controlled is a requirement if we are to predict how they evolve and how they might respond to selection. This requires understanding how distinct, and often more simple, life history traits interact and change in response to environmental conditions. In order to begin addressing such issues, we have been analyzing the formation of the developmentally arrested dauer larvae of Caenorhabditis elegans under different conditions.ResultsWe find that 18 of 22 previously identified quantitative trait loci (QTLs) affecting dauer larvae formation in growing populations, assayed by determining the number of dauer larvae present at food patch exhaustion, can be recovered under various environmental conditions. We also show that food patch size affects both the ability to detect QTLs and estimates of effect size, and demonstrate that an allele of nath-10 affects dauer larvae formation in growing populations. To investigate the component traits that affect dauer larvae formation in growing populations we map, using the same introgression lines, QTLs that affect dauer larvae formation in response to defined amounts of pheromone. This identifies 36 QTLs, again demonstrating the highly polygenic nature of the genetic variation underlying dauer larvae formation.ConclusionsThese data indicate that QTLs affecting the number of dauer larvae at food exhaustion in growing populations of C. elegans are highly reproducible, and that nearly all can be explained by variation affecting dauer larvae formation in response to defined amounts of pheromone. This suggests that most variation in dauer larvae formation in growing populations is a consequence of variation in the perception of the food and pheromone environment (i.e. chemosensory variation) and in the integration of these cues.
For species that rely on ephemeral resources, genotype fitness will depend on traits that affect both population growth rates and dispersal. Understanding how such traits are related is central to understanding how they may evolve. Natural populations of Caenorhabditis elegans exhibit rapid population growth within resource-rich patches of decaying organic material and subsequent dispersal, primarily as developmentally-arrested dauer larvae, between patches. The properties of growing populations of C. elegans are, however, poorly understood. Here we show that food availability, dauer pheromone (a measure of conspecific population density) and temperature affect dauer larvae development in growing populations as would be predicted from analyses of single cohorts of worms. We also show that as food patch size increases, dauer larvae are formed prior to patch exhaustion and that the number of dauer larvae present increases after the patch is exhausted, i.e., worms that had not completed development as dauer larvae when the food was exhausted continue development in the absence of bacterial food. Crucially, the subsequent reproductive fitness of dauer larvae that complete development after the exhaustion of the bacterial food patch is reduced in comparison with dauer larvae that develop prior to patch exhaustion. These results demonstrate that population level analyses of C. elegans are feasible, support previous studies of the environmental factors affecting dauer larvae development and suggest an adaptive benefit for variation between isolates in the sensitivity of dauer larvae development.
Developmental decisions are important in organismal fitness. For the nematode Caenorhabditis elegans, which is naturally found in the ephemeral food patches formed by rotting plant material, correctly committing to dauer or non-dauer larval development is key to genotype survival. To investigate the link between reproductive traits, which will determine how populations grow, and dauer larvae formation, we have analysed these traits in mutation accumulation lines of C. elegans. We find that reproductive traits of individual worms-the total number of progeny and the timing of progeny production-are highly correlated with the population size observed in growing populations. In contrast, we find no relationship between reproduction traits and the number of dauer larvae observed in growing populations. We also do not observe a mutational bias in dauer larvae formation. These results indicate that the control of dauer larvae formation is distinct from the control of reproduction and that differences in dauer larvae formation can evolve rapidly.
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