# Hyperactivation of mTORC1 by an endogenous raga-1 gain-of-function mutation does not reduce lifespan in C. elegans

## TL;DR

A study in C. elegans finds that hyperactivating mTORC1 through a specific mutation does not shorten lifespan, challenging previous assumptions about mTORC1's role in aging.

## Contribution

The study demonstrates that endogenous mTORC1 hyperactivation in C. elegans does not reduce lifespan, suggesting compensatory mechanisms may exist.

## Key findings

- Transgenic expression of rag-1[Q63L] reduces lifespan without mTORC1 hyperactivation.
- CRISPR-generated rag-1[Q63L] hyperactivates mTORC1 without affecting lifespan.
- Genetic context and compensatory mechanisms may influence mTORC1's role in lifespan regulation.

## Abstract

Inhibition of mTORC1, a conserved nutrient-sensing complex, extends lifespan across model organisms, but the effects of mTORC1 hyperactivation are less understood. RagA, a GTPase essential for mTORC1 activation, can be locked in its active GTP-bound state through gain-of-function mutations, such as Q63L in
C.
elegans
RAGA-1. We found that transgenic expression of
raga-1[Q63L]
mutation (
egIs12
) decreases lifespan without hyperactivating mTORC1, suggesting mTORC1-independent effects or transgene toxicity. In contrast, we show that a CRISPR-generated Q63L mutation at the endogenous
raga-1
locus (
viz128)
hyperactivates mTORC1 without affecting lifespan, challenging the paradigm that mTORC1 hyperactivation accelerates aging. Thus, genetic context and potential compensatory mechanisms may contribute to mTORC1-mediated lifespan regulation, at least in metazoans.