TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO

By Stacey Robida-Stubbs, Kira Glover-Cutter, Dudley Lamming, Masaki Mizunuma, S. Narasimhan, Elke Neumann-Haefelin, David M. Sabatini, T. Blackwell. Cell Metabolism, 2012

624 citations recorded by the source corpus.

Summary The TOR kinase, which is present in the functionally distinct complexes TORC1 and TORC2, is essential for growth but associated with disease and aging. Elucidation of how TOR modulates lifespan will identify mechanisms of fundamental importance in aging, and TOR functions. Here we show that when TORC1 is inhibited genetically in C. elegans, SKN-1/Nrf and DAF-16/FoxO activate protective genes, and increase stress resistance and longevity. SKN-1 also upregulates TORC1 pathway gene expression in a feedback loop. Rapamycin triggers a similar protective response in C. elegans and mice but increases worm lifespan dependent upon SKN-1 and not DAF-16, apparently by interfering with TORC2 along with TORC1. TORC1, TORC2, and insulin/IGF-1-like signaling regulate SKN-1 activity through different mechanisms. We conclude that modulation of SKN-1/Nrf and DAF-16/FoxO may be generally important in the effects of TOR signaling in vivo, and that these transcription factors mediate an opposing relationship between growth signals and longevity.

Subfields: Aging, Endocrine and Autonomic Systems, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/578ca40ff11fb1c0aeac0c26e93408a3f1b5c3c7

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Citations in the corpus

Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism (2016, background): “SKN-1 is also involved in lifespan extensions in response to reduced activity of the mechanistic target of rapamycin (mTOR) signaling [120, 121].”
mTOR Signaling in Growth, Metabolism, and Disease. (2017, background): “Consistent with this, the mTOR inhibitor rapamycin is currently the only pharmacological treatment proven to extend life span in all of these model organisms (Bjedov et al., 2010; Harrison et al., 2009; Powers et al., 2006; Robida-Stubbs et al., 2012).”
Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease (2023, background): “172 – 174 This is well-established that mTORC1 has a major role in nutrients and insulin sensing.”
Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease (2015, positive): “Stimulation of mTOR through insulin signaling has been shown in Caenorhabditis elegans to lead to the induction of SKN-1 and DAF-16 (the mammalian orthologs of which are Nrf2 and FOXO, respectively) target genes that protect cells by diminishing metabolic stress [459].”
mTOR Signaling in Growth, Metabolism, and Disease (2017, background): “Consistent with this, the mTOR inhibitor rapamycin is currently the only pharmacological treatment proven to extend lifespan in all of these model organisms (Bjedov et al., 2010; Harrison et al., 2009; Powers et al., 2006; Robida-Stubbs et al., 2012).”
Ageing as a risk factor for disease. (2012, background): “Rapamycin inhibits mTOR, and can increase lifespan in worms, flies and mice [49,118].”