Neuronal mTORC1 inhibition promotes longevity without suppressing anabolic growth and reproduction in C. elegans

mTORC1 (mechanistic target of rapamycin complex 1) is a metabolic sensor that promotes growth when nutrients are abundant. Ubiquitous inhibition of mTORC1 extends lifespan in multiple organisms but also disrupts several anabolic processes resulting in stunted growth, slowed development, reduced fertility, and disrupted metabolism. However, it is unclear if these pleotropic effects of mTORC1 inhibition can be uncoupled from longevity. Here, we utilize the auxin-inducible degradation (AID) system to restrict mTORC1 inhibition to C. elegans neurons. We find that neuron-specific degradation of RAGA-1, an upstream activator of mTORC1, or LET-363, the ortholog of mammalian mTOR, is sufficient to extend lifespan in C. elegans. Unlike raga-1 loss of function genetic mutations or somatic AID of RAGA-1, neuronal AID of RAGA-1 robustly extends lifespan without impairing body size, developmental rate, brood size or neuronal function. Moreover, while somatic degradation of RAGA-1 alters the expression of thousands of genes, demonstrating the widespread effects of mTORC1 inhibition, neuronal degradation of RAGA-1 only results in around 200 differentially expressed genes with a specific enrichment in metabolism and stress response. Notably, our work demonstrates that targeting mTORC1 specifically in the nervous system in C. elegans uncouples longevity from growth and reproductive impairments, and that many canonical effects of low mTORC1 activity are not required to promote healthy aging. These data challenge previously held ideas about the mechanisms of mTORC1 lifespan extension and underscore the potential of promoting longevity by neuron-specific mTORC1 modulation. Overall design: To compare the effects of knocking down RAGA-1 in either the neurons or all somatic tissues, we generated C. elegans strains in which endogenous raga-1 was tagged with an auxin-inducible degron tag. We then expressed the degrading enzyme, TIR1, in either the neurons (1250) or all somatic (1438) tissues using the rab-3 and eft-3 promoters, respectively. In these two strains along with wild type worms (N2), we began auxin treatment at day 1 of adulthood to induce RAGA-1 degradation in either the neurons or in all somatic tissues and then harvested RNA from whole worm lysate 2 days later. We then performed RNA sequencing and differential gene expression analysis to compare gene expression changes between auxin-treated (A) and untreated samples (C) from each genotype. 4 replicates of all 6 samples were performed.