CGEF-1 regulates mTORC1 signaling during adult longevity and stress response in C. elegans

Abstract

The mechanistic target of rapamycin (mTOR) kinase is central to metabolism and growth, and has a conserved role in aging. mTOR functions in two complexes, mTORC1 and mTORC2. In diverse eukaryotes, inhibition of mTORC1 signaling increases lifespan. mTORC1 transduces anabolic signals to stimulate protein synthesis and inhibits autophagy. In this study, we demonstrate that CGEF-1, the C. elegans homolog of the human guanine nucleotide exchange factor Dbl, is a novel binding partner of RHEB-1 and activator of mTORC1 signaling in C. elegans. cgef-1 mutants display prolonged lifespan and enhanced stress resistance. The transcription factors DAF-16/FoxO and SKN-1/Nrf are required for increased longevity and stress tolerance, and induce protective gene expression in cgef-1 mutants. Genetic evidence indicates that cgef-1 functions in the same pathway with rheb-1, the mTOR kinase let-363, and daf-15/Raptor. When cgef-1 is inactivated, phosphorylation of 4E-BP, a central mTORC1 substrate for protein translation is reduced in C. elegans. Moreover, autophagy is increased upon cgef-1 and mTORC1 inhibition. In addition, we show that in human cells Dbl associates with Rheb and stimulates mTORC1 downstream targets for protein synthesis suggesting that the function of CGEF-1/Dbl in the mTORC1 signaling pathway is evolutionarily conserved. These findings have important implications for mTOR functions and signaling mechanisms in aging and age-related diseases.

TOR Signaling in Caenorhabditis elegans Development, Metabolism, and Aging

“…These effects on gene expression were distinct from those that occur in response to reduced IIS. By several criteria, the effects of TORC1 inhibition on life span, stress resistance, and transcription were mimicked by inactivation of CGEF-1, a guanine nucleotide exchange factor that physically interacts with RHEB-1 in cell culture assays, and thus may be a new player in TORC1 signaling (Li et al 2018). Together, the data suggest that SKN-1/Nrf-and DAF-16/FOXO-mediated transcriptional programs are critical for life span extension from reduced TORC1 activity, and are induced in response to reduced translation.…”

Nurturing longevity through natural compounds: Where do we stand, and where do we go?

“…The mTOR pathway has garnered significant research attention in the context of metabolism, as it functions as a mediator of the cellular processes of anabolism and catabolism when nutrients are available. Modulating this pathway, such as through the molecule rapamycin (Bitto et al., 2016; Hurez et al., 2015), has been found to extend lifespan and promote healthspan benefits in various species (Goldberg et al., 2015; Yujie Li et al., 2018; Statzer et al., 2022; Yue Zhang et al., 2019). The mTOR kinase exists in two complexes: mTORC1, which is linked to autophagy (Statzer et al., 2022), and mTORC2, which is regulated by IGF signaling and the pathway (Sural‐Fehr et al., 2019).…”

“…Moreover, the two complexes interact with different players of the nutrient‐sensing network, including AMPK (Yue Zhang et al., 2019). While inhibiting mTORC1 signaling has been associated with longevity benefits (Statzer et al., 2022; Yue Zhang et al., 2019), it is worth noting that the lifespan of the roundworm C. elegans can be extended through either mTORC1 or mTORC2 individually (Yujie Li et al., 2018; Mizunuma et al., 2014).…”