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

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.