Erratum: Corrigendum: Splicing factor 1 modulates dietary restriction and TORC1 pathway longevity in C. elegans

Heintz, Caroline; Doktor, Thomas Koed; Lanjuin, Anne; Escoubas, Caroline C.; Zhang, Yue; Weir, Heather J.; Dutta, Sneha; Silva-García, Carlos Giovanni; Bruun, Georg M.; Morantte, Ianessa; Hoxhaj, Gerta; Manning, Brendan D.; Andresen, Brage Storstein; Mair, William B.

doi:10.1038/nature23313

Cited by 4 publications

(2 citation statements)

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“…The quality of RNA control mechanisms, such as non-sense-mediated mRNA decay (NMD) activity in various organs and tissues, decline with advancing age in C. elegans . Also, the increased levels of introns and unannotated regions in the mRNAs denote a decrease of mRNA splicing fidelity in aged worms ( 19 ). Protein homeostasis associated with age-related diseases declines during aging ( 20 ).…”

Section: Background Advantages and Limitations Of C Elegmentioning

confidence: 99%

Caenorhabditis elegans as a Useful Model for Studying Aging Mutations

et al. 2020

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The Caenorhabditis elegans genome possesses homologs of about two-thirds of all human disease genes. Based on its physiological aging characteristics and superiority, the use of C. elegans as a model system for studies on aging, age-related diseases, mechanisms of longevity, and drug screening has been widely acknowledged in recent decades. Lifespan increasing mutations in C. elegans were found to delay aging by impinging several signaling pathways and related epigenetic modifications, including the insulin/IGF-1 signaling (IIS), AMP-activated protein kinase (AMPK), and mechanistic target of rapamycin (mTOR) pathways. Interestingly, dietary restriction (DR) has been shown to increase the lifespan of numerous metazoans and protect them from multiple age-related pathologies. However, the underlying molecular mechanisms are unclear. In recent decades, C. elegans has been used as a unique model system for high-throughput drug screening. Here, we review C. elegans mutants exhibiting increased in lifespan and age-dependent changes under DR, as well as the utility of C. elegans for drug screening. Thus, we provide evidence for the use of this model organism in research on the prevention of aging.

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Section: Background Advantages and Limitations Of C Elegmentioning

confidence: 99%

Caenorhabditis elegans as a Useful Model for Studying Aging Mutations

et al. 2020

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“…Similarly, methionine restriction extends eukaryotic life span probably through a mechanism involved in H 2 S production as well [8]. Mechanistic target of rapamycin complex 1 (mTORC1) pathway also plays a key role in the anti-aging effects of DR [9, 10]. Inhibiting mTORC1 pathway by rapamycin treatment or by deletion of down-stream signaling components such as SCH9 , an homologue of mammalian S6K1 in Saccharomyces cerevisiae and one of direct substrates of mTORC1, mimics DR and provides anti-aging benefits [11–13].…”

Section: Introductionmentioning

confidence: 99%

mTORC1-Sch9 regulates hydrogen sulfide production through the transsulfuration pathway

Zhou

Gao

Wang

et al. 2019

Aging

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Endogenous hydrogen sulfide mediates anti-aging benefits of dietary restriction (DR). However, it is unclear how H2S production is regulated by pathways related to DR. Due to the importance of mTORC1 pathway in DR, we investigated the effects of Sch9, a yeast homolog of mammalian S6K1 and a major substrate of mTORC1 on H2S production in yeast Saccharomyces cerevisiae. We found that inhibition of the mTORC1-Sch9 pathway by SCH9 deletion, rapamycin or myriocin treatment resulted in a dramatic decrease in H2S production. Although deficiency of SCH9 did not alter the intracellular level of methionine, the intracellular level of cysteine increased in Δsch9 cells. The expression of CYS3 and CYS4, two transsulfuration pathway genes encoding cystathionine gamma-lyase (CGL) and cystathionine beta-synthase (CBS), were also decreased under mTORC1-Sch9 inhibition. Overexpression of CYS3 or CYS4 in Δsch9 cells or WT cells treated with rapamycin rescued the deficiency of H2S production. Finally, we also observed a reduction in H2S production and lowering of both mRNA and protein levels of CGL and CBS in cultured human cells treated with rapamycin to reduce mTORC1 pathway activity. Thus, our findings reveal a probably conserved mechanism in which H2S production by the transsulfuration pathway is regulated by mTORC1-Sch9 signaling.

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Efficacy of longevity interventions in C. elegans is determined by early life activity of RNA splicing factors

Dutta

Heintz

et al. 2021

Preprint

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Geroscience aims to target the aging process to extend healthspan. However, even isogenic individuals show heterogeneity in natural aging rate and responsiveness to pro-longevity interventions, limiting translational potential. Using in vivo mini gene reporters in isogenic C. elegans, we show that alternative splicing of mRNAs related to lipid metabolism in young animals is coupled to subsequent life expectancy. Further, activity of RNA splicing factors REPO-1 and SFA-1 early in life modulates effectiveness of specific longevity interventions via POD-2/ACC1 and regulation of lipid utilization. In addition, early inhibition of REPO-1 renders animals refractory to late onset suppression of the TORC1 pathway. Together these data suggest that activity of RNA splicing factors and the metabolic landscape early in life can modulate responsiveness to longevity interventions and may explain variance in efficacy between individuals.One Sentence SummaryEfficacy of pro-longevity interventions in C. elegans is determined by the activity of splicing factors and the lipid metabolic landscape early in the life of the individual.

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Erratum: Corrigendum: Splicing factor 1 modulates dietary restriction and TORC1 pathway longevity in C. elegans

Cited by 4 publications

References 1 publication

Caenorhabditis elegans as a Useful Model for Studying Aging Mutations

Caenorhabditis elegans as a Useful Model for Studying Aging Mutations

mTORC1-Sch9 regulates hydrogen sulfide production through the transsulfuration pathway

Efficacy of longevity interventions in C. elegans is determined by early life activity of RNA splicing factors

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