| Abstrakt: |
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 degradation of RAGA-1 in all somatic tissues alters the expression of thousands of genes, demonstrating the widespread effects of mTORC1 inhibition, degradation of RAGA-1 in neurons 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. Author summary: Inhibition of the metabolic pathway mTORC1 has been shown to extend lifespan in many organisms and has gained traction as a possible anti-aging therapeutic. However, in addition to lifespan extension, chronic and body-wide mTORC1 inhibition results in a downregulation of anabolic processes that leads to unwanted side effects such as impaired growth, development, and reproduction in C. elegans, Drosophila melanogaster, and mice. An open question in the field is if mTORC1 inhibition can be restricted to specific tissues to promote longevity while minimizing the anabolic trade-offs. In this study, we test this hypothesis using the model organism C. elegans and the auxin-inducible degradation (AID) system which provides many advantages over previous techniques used to study the tissue-specificity of mTORC1 in aging. We find that degradation of mTORC1 pathway components specifically in the neurons robustly extends lifespan while preserving normal growth, development, and reproduction. Furthermore, we find that animals with neuronal mTORC1 inhibition maintain functional sensory neurons and have changes in the expression of genes related to stress response and metabolism. This work challenges previously held theories that anabolic trade-offs are required for mTORC1 longevity and highlights a critical role for neuronal mTORC1 in the regulation of organismal aging. [ABSTRACT FROM AUTHOR] |
