Targeting mTORC1 in the neurons to promote healthy aging in C. elegans

Abstract

One of the goals of aging research is to develop drugs and interventions that can move out of the lab and into human health care to promote longer and healthier lives. Currently, many of the interventions that are the most successful at extending lifespan also have serious trade-offs that limit their translational potential. For example, inhibition of the metabolic pathway mTORC1 (mechanistic target of rapamycin complex 1) extends lifespan in many organisms but also results in impaired growth and development. In my thesis research, I show that neuron-specific degradation of RAGA-1, an upstream activator of mTORC1, robustly extends the lifespan of C. elegans without causing the impaired reproduction and growth associated with whole-body mTORC1 inhibition. Neuronal degradation of RAGA-1 upregulates genes involved in stress response and fluorescent imaging revealed that the superoxide dismutase SOD-3 was upregulated in the intestine, demonstrating cell nonautonomous effects of neuron-specific mTORC1 modulation. Knockdown of various genes involved in neurotransmitter biosynthesis, neurotransmitter release, and neuropeptide released did not suppress the longevity mediated by neuronal RAGA-1 degradation, leaving open questions regarding the signaling mechanisms between the neurons and peripheral tissues. Although further research is required to strengthen our knowledge regarding the mechanisms by which neuronal mTORC1 inhibition regulate lifespan, the research presented in this thesis highlights tissue-specific targeting of metabolic pathways as a promising strategy to promote healthy aging.