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...

Source: Fight Aging! - October 6, 2023 Category: Research Authors: Reason Tags: Daily News Source Type: blogs