mTORC1 Inhibition in Neurons Only Extends Life in Nematode Worms

General inhibition of mTOR slows aging, a calorie restriction mimetic effect, but comes with a range of side-effects, given that mTOR is a regulator of growth and development. mTOR forms two different protein complexes, mTORC1 and mTORC2. In recent years, work to produce drugs based on mTOR inhibition has focused on selectively inhibiting mTORC1 in order to reduce side-effects. Researchers here report further reduction in side-effects in short-lived nematode worms by restricting mTORC1 inhibition to neurons only.

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 pleiotropic 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. This data challenges previously held ideas about the mechanisms of mTORC1 lifespan extension and underscore the potential of promoting longevity by neuron-specific mTORC1 modulation.



mTORC1 Inhibition in Neurons Only Extends Life in Nematode Worms
need punctuation?
mTORC1 Inhibition in Neurons-Only Extends Life in Nematode Worms
mTORC1 Inhibition in Neurons Only, Extends Life in Nematode Worms
mTORC1 Inhibition in Neurons-Only, Extends Life in Nematode Worms
because i read it as
mTORC1 Inhibition in Neurons
Only Extends Life in Nematode Worms

Posted by: Rob at October 6th, 2023 9:57 AM

An entire industry focused on the control and eradication of these agricultural pests and some mad scientists are trying to extend their lives !

Posted by: Tom Schaefer at October 9th, 2023 10:19 AM

Tom - While there are at least 2 types of parasitic nematodes known to damage crops, C. elegans are neither parasitic nor an agricultural threat. Rather, they are one of the most powerful model organisms to study aging. Aging researchers are not interested in extending lives of animals, but want to uncover the biological basis of aging so that we can live healthier lives in old age. Maybe, try considering the context before writing an uninformed comment that totally misses the point.

Posted by: Jo at October 13th, 2023 3:01 PM
Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.