scholarly journals Neuronal mTORC1 inhibition promotes longevity without suppressing anabolic growth and reproduction in C. elegans

2021 ◽  
Author(s):  
Hannah J Smith ◽  
Anne Lanjuin ◽  
Arpit Sharma ◽  
Aditi Prabhakar ◽  
Emina Tabakovic ◽  
...  
Keyword(s):  
Somatic Tissue ◽  
Reproductive Capacity ◽  
Null Mutant ◽  
Similar Extent ◽  
Stunted Growth ◽  
C Elegans ◽  
Slow Development ◽  
Metabolic Sensor ◽  
Neuronal Degradation ◽  
Growth And Reproduction

One of the most robust and reproducible methods to prolong lifespan in a variety of organisms is inhibition of the mTORC1 (mechanistic target of rapamycin complex 1) pathway. mTORC1 is a metabolic sensor that promotes anabolic growth when nutrients are abundant. Inhibition of mTORC1 extends lifespan, but also frequently has other effects such as stunted growth, slowed development, reduced fertility, and disrupted metabolism. It has long been assumed that suppression of anabolism and resulting phenotypes such as impaired growth and reproduction may be causal to mTORC1 longevity, but this hypothesis has not been directly tested. RAGA-1 is an upstream activator of TORC1. Previous work from our lab using a C. elegans model of mTORC1 longevity, the long-lived raga-1 null mutant, found that the presence of RAGA-1 only in the neurons suppresses longevity of the null mutant. Here, we use the auxin-inducible degradation (AID) system to test whether neuronal mTORC1 inhibition is sufficient for longevity, and whether any changes in lifespan are also linked to stunted growth or fertility. We find that life-long AID of RAGA-1 either in all somatic tissue or only in the neurons of C. elegans is sufficient to extend lifespan. We also find that AID of RAGA-1 or LET-363/mTOR beginning at day 1 of adulthood extends lifespan to a similar extent. Unlike somatic degradation of RAGA-1, neuronal degradation of RAGA-1 does not impair growth, slow development, or decrease the reproductive capacity of the worms. Lastly, while AID of LET-363/mTOR in all somatic cells shortens lifespan, neuronal AID of LET-363/mTOR promotes longevity. This work demonstrates that targeting mTORC1 specifically in the neurons uncouples longevity from growth and reproductive impairments, challenging previously held ideas about the mechanisms of mTORC1 longevity and elucidating the promise of tissue-specific aging therapeutics.

Frequent Germline Mutations and Somatic Repeat Instability in DNA Mismatch-Repair-Deficient Caenorhabditis elegans

Genetics ◽  
2002 ◽  
Vol 161 (2) ◽  
pp. 651-660
Author(s):  
Marcel Tijsterman ◽  
Joris Pothof ◽  
Ronald H A Plasterk
Keyword(s):  
Caenorhabditis Elegans ◽  
Mismatch Repair ◽  
Large Scale ◽  
Somatic Tissue ◽  
Repeat Instability ◽  
Dna Mismatch ◽  
C Elegans ◽  
Colon Cancers ◽  
Dna Repeat ◽  
Female Germline

Abstract Mismatch-repair-deficient mutants were initially recognized as mutation-prone derivatives of bacteria, and later mismatch repair deficiency was found to predispose humans to colon cancers (HNPCC). We generated mismatch-repair-deficient Caenorhabditis elegans by deleting the msh-6 gene and analyzed the fidelity of transmission of genetic information to subsequent generations. msh-6-defective animals show an elevated level of spontaneous mutants in both the male and female germline; also repeated DNA tracts are unstable. To monitor DNA repeat instability in somatic tissue, we developed a sensitive system, making use of heat-shock promoter-driven lacZ transgenes, but with a repeat that puts this reporter gene out of frame. In genetic msh-6-deficient animals lacZ+ patches are observed as a result of somatic repeat instability. RNA interference by feeding wild-type animals dsRNA homologous to msh-2 or msh-6 also resulted in somatic DNA instability, as well as in germline mutagenesis, indicating that one can use C. elegans as a model system to discover genes involved in maintaining DNA stability by large-scale RNAi screens.

scholarly journals Ferrous-glutathione coupling mediates ferroptosis and frailty in Caenorhabditis elegans

2019 ◽  
Author(s):  
Nicole L. Jenkins ◽  
Simon A. James ◽  
Agus Salim ◽  
Fransisca Sumardy ◽  
Terence P. Speed ◽  
...  
Keyword(s):  
Cell Death ◽  
Caenorhabditis Elegans ◽  
Ferrous Iron ◽  
Somatic Tissue ◽  
Glutathione Depletion ◽  
Death Process ◽  
C Elegans ◽  
Regulated Cell Death ◽  
Age Related ◽  
Ageing Rate

All eukaryotes require iron. Replication, detoxification, and a cancer-protective form of regulated cell death termed ferroptosis1, all depend on iron metabolism. Ferrous iron accumulates over adult lifetime in the Caenorhabditis elegans model of ageing2. Here we show that glutathione depletion is coupled to ferrous iron elevation in these animals, and that both occur in late life to prime cells for ferroptosis. We demonstrate that blocking ferroptosis, either by inhibition of lipid peroxidation or by limiting iron retention, mitigates age-related cell death and markedly increases lifespan and healthspan in C. elegans. Temporal scaling of lifespan is not evident when ferroptosis is inhibited, consistent with this cell death process acting at specific life phases to induce organismal frailty, rather than contributing to a constant ageing rate. Because excess age-related iron elevation in somatic tissue, particularly in brain3–5, is thought to contribute to degenerative disease6, 7, our data indicate that post-developmental interventions to limit ferroptosis may promote healthy ageing.

Regulation of ectodermal and excretory function by the C. elegans POU homeobox gene ceh-6

Development ◽  
2001 ◽  
Vol 128 (5) ◽  
pp. 779-790 ◽  
Author(s):  
T.R. Burglin ◽  
G. Ruvkun
Keyword(s):  
Transcription Factor ◽  
Epithelial Cells ◽  
Homeobox Genes ◽  
Homeobox Gene ◽  
Null Mutant ◽  
Reporter Construct ◽  
Excretory Function ◽  
C Elegans ◽  
Gfp Reporter ◽  
Excretory Cell

Caenorhabditis elegans has three POU homeobox genes, unc-86, ceh-6 and ceh-18. ceh-6 is the ortholog of vertebrate Brn1, Brn2, SCIP/Oct6 and Brn4 and fly Cf1a/drifter/ventral veinless. Comparison of C. elegans and C. briggsae CEH-6 shows that it is highly conserved. C. elegans has only three POU homeobox genes, while Drosophila has five that fall into four families. Immunofluorescent detection of the CEH-6 protein reveals that it is expressed in particular head and ventral cord neurons, as well as in rectal epithelial cells, and in the excretory cell, which is required for osmoregulation. A deletion of the ceh-6 locus causes 80% embryonic lethality. During morphogenesis, embryos extrude cells in the rectal region of the tail or rupture, indicative of a defect in the rectal epithelial cells that express ceh-6. Those embryos that hatch are sick and develop vacuoles, a phenotype similar to that caused by laser ablation of the excretory cell. A GFP reporter construct expressed in the excretory cell reveals inappropriate canal structures in the ceh-6 null mutant. Members of the POU-III family are expressed in tissues involved in osmoregulation and secretion in a number of species. We propose that one evolutionary conserved function of the POU-III transcription factor class could be the regulation of genes that mediate secretion/osmoregulation.

scholarly journals A Dihydroflavonoid Naringin Extends the Lifespan of C. elegans and Delays the Progression of Aging-Related Diseases in PD/AD Models via DAF-16

2020 ◽  
Vol 2020 ◽  
pp. 1-14 ◽  
Author(s):  
Qing Zhu ◽  
Yuan Qu ◽  
Xiao-Gang Zhou ◽  
Jian-Ning Chen ◽  
Huai-Rong Luo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stem Cells ◽  
Biological Activities ◽  
Nutrient Sensing ◽  
Null Mutant ◽  
Oxidative Stress Tolerance ◽  
C Elegans ◽  
Expression Of Genes ◽  
Wide Range ◽  
And Oxidative Stress

Naringin is a dihydroflavonoid, which is rich in several plant species used for herbal medicine. It has a wide range of biological activities, including antineoplastic, anti-inflammatory, antiphotoaging, and antioxidative activities. So it would be interesting to know if naringin has an effect on aging and aging-related diseases. We examined the effect of naringin on the aging of Caenorhabditis elegans (C. elegans). Our results showed that naringin could extend the lifespan of C. elegans. Moreover, naringin could also increase the thermal and oxidative stress tolerance, reduce the accumulation of lipofuscin, and delay the progress of aging-related diseases in C. elegans models of AD and PD. Naringin could not significantly extend the lifespan of long-lived mutants from genes in insulin/IGF-1 signaling (IIS) and nutrient-sensing pathways, such as daf-2, akt-2, akt-1, eat-2, sir-2.1, and rsks-1. Naringin treatment prolonged the lifespan of long-lived glp-1 mutants, which have decreased reproductive stem cells. Naringin could not extend the lifespan of a null mutant of the fox-head transcription factor DAF-16. Moreover, naringin could increase the mRNA expression of genes regulated by daf-16 and itself. In conclusion, we show that a natural product naringin could extend the lifespan of C. elegans and delay the progression of aging-related diseases in C. elegans models via DAF-16.

scholarly journals The Caenorhabditis elegans Replication Licensing Factor CDT-1 Is Targeted for Degradation by the CUL-4/DDB-1 Complex

2006 ◽  
Vol 27 (4) ◽  
pp. 1394-1406 ◽  
Author(s):  
Youngjo Kim ◽  
Edward T. Kipreos
Keyword(s):  
Caenorhabditis Elegans ◽  
Ubiquitin Ligase ◽  
S Phase ◽  
Null Mutant ◽  
Wild Type ◽  
C Elegans ◽  
Licensing Factor ◽  
Ubiquitin Ligase E3 ◽  
Blast Cells ◽  
Temporal Restriction

ABSTRACT The replication of genomic DNA is strictly regulated to occur only once per cell cycle. This regulation centers on the temporal restriction of replication licensing factor activity. Two distinct ubiquitin ligase (E3) complexes, CUL4/DDB1 and SCFSkp2, have been reported to target the replication licensing factor Cdt1 for ubiquitin-mediated proteolysis. However, it is unclear to what extent these two distinct Cdt1 degradation pathways are conserved. Here, we show that Caenorhabditis elegans DDB-1 is required for the degradation of CDT-1 during S phase. DDB-1 interacts specifically with CUL-4 but not with other C. elegans cullins. A ddb-1 null mutant exhibits extensive DNA rereplication in postembryonic BLAST cells, similar to what is observed in cul-4(RNAi) larvae. DDB-1 physically associates with CDT-1, suggesting that CDT-1 is a direct substrate of the CUL-4/DDB-1 E3 complex. In contrast, a deletion mutant of the C. elegans Skp2 ortholog, skpt-1, appears overtly wild type with the exception of an impenetrant gonad migration defect. There is no appreciable role for SKPT-1 in the degradation of CDT-1 during S phase, even in a sensitized ddb-1 mutant background. We propose that the CUL-4/DDB-1 ubiquitin ligase is the principal E3 for regulating the extent of DNA replication in C. elegans.

scholarly journals Null Mutation in Transforming Growth Factor β1 Disrupts Ovarian Function and Causes Oocyte Incompetence and Early Embryo Arrest

Endocrinology ◽  
2006 ◽  
Vol 147 (2) ◽  
pp. 835-845 ◽  
Author(s):  
Wendy V. Ingman ◽  
Rebecca L. Robker ◽  
Karen Woittiez ◽  
Sarah A. Robertson
Keyword(s):  
Transforming Growth Factor ◽  
Ovarian Function ◽  
Mutant Mice ◽  
Reproductive Capacity ◽  
Null Mutation ◽  
Null Mutant ◽  
Critical Determinant ◽  
Serum Progesterone ◽  
Null Mutant Mice

TGFβ1 is implicated in regulation of ovarian function and the events of early pregnancy. We have investigated the effect of null mutation in the Tgfβ1 gene on reproductive function in female mice. The reproductive capacity of TGFβ1 null mutant females was severely impaired, leading to almost complete infertility. Onset of sexual maturity was delayed, after which ovarian function was disrupted, with extended ovarian cycles, irregular ovulation, and a 40% reduction in oocytes ovulated. Serum FSH and estrogen content were normal, but TGFβ1 null mutant mice failed to display the characteristic proestrus surge in circulating LH. Ovarian hyperstimulation with exogenous gonadotropins elicited normal ovulation rates in TGFβ1 null mutant mice. After mating with wild-type stud males, serum progesterone content was reduced by 75% associated with altered ovarian expression of mRNAs encoding steroidogenic enzymes 3β-hydroxysteroid dehydrogenase-1 and P450 17 α-hydroxylase/C17–20-lyase. Embryos recovered from TGFβ1 null mutant females were developmentally arrested in the morula stage and rarely progressed to blastocysts. Attempts to rescue embryos by exogenous progesterone administration and in vitro culture were unsuccessful, and in vitro fertilization and culture experiments demonstrated that impaired development is unlikely to result from lack of maternal tract TGFβ1. We conclude that embryo arrest is due to developmental incompetence in oocytes developed in a TGFβ1-deficient follicular environment. This study demonstrates that TGFβ1 is a critical determinant of normal ovarian function, operating through regulation of LH activity and generation of oocytes competent for embryonic development and successful initiation of pregnancy.

Effects of the antibiotic tetracycline on the reproduction, growth and population growth rate of the nematode Caenorhabditis elegans

Nematology ◽  
2014 ◽  
Vol 16 (1) ◽  
pp. 19-29 ◽  
Author(s):  
Matthew Vangheel ◽  
Walter Traunspurger ◽  
Nicole Spann
Keyword(s):  
Growth Rate ◽  
Caenorhabditis Elegans ◽  
Population Growth ◽  
Surface Waters ◽  
Population Growth Rate ◽  
Significant Risk ◽  
Protein Synthesis Inhibitors ◽  
Natural Systems ◽  
C Elegans ◽  
Growth And Reproduction

The antibiotic tetracycline (TC) has been reported in natural systems, a consequence of its abundant usage in farming. TCs are protein synthesis inhibitors that are effective against bacteria but adverse effects on non-target organisms, whilst less well understood, have also been demonstrated. This study is the first investigation into the effects of this common antibiotic on the growth, reproduction and population growth rate (PGR) of the nematode Caenorhabditis elegans. All toxicological endpoints were shown to be affected negatively. TC concentrations as low as 5 mg l−1 (5 ppm) significantly reduced growth and reproduction, and even lower concentrations (3 mg l−1 or 3 ppm) significantly decreased the PGR. These levels are much higher than the TC concentrations detected in surface waters, sediments and soils (0.005-300 ppb). However, although the antibiotic might not pose a direct significant risk to nematodes in the natural environment, its use in RNAi experiments involving C. elegans may cause unwanted effects that influence interpretations of the results.

scholarly journals Two parallel pathways are required for ultrasound-evoked behavioral changes in Caenorhabditis elegans

2021 ◽  
Author(s):  
Uri Magaram ◽  
Connor Weiss ◽  
Aditya Vasan ◽  
Kirthi C Reddy ◽  
James Friend ◽  
...  
Keyword(s):  
Double Mutant ◽  
Behavioral Responses ◽  
Behavioral Changes ◽  
Mechanosensitive Channel ◽  
Ultrasound Transducer ◽  
Null Mutant ◽  
Behavioral Deficit ◽  
C Elegans ◽  
Msec Pulse ◽  
Molecular Machinery

Ultrasound has been shown to affect the function of both neurons and non-neuronal cells. However, the underlying molecular machinery has been poorly understood. Here, we show that at least two mechanosensitive proteins act in parallel to generate C. elegans behavioral responses to ultrasound stimuli. We first show that these animals generate reversals in response to a single 10 msec pulse from a 2.25 MHz ultrasound transducer. Next, we show that the pore-forming subunit of the mechanosensitive channel TRP-4, and a DEG/ENaC/ASIC ion channel MEC-4, are both required for this ultrasound-evoked reversal response. Further, the trp-4 mec-4 double mutant shows a stronger behavioral deficit compared to either single mutant. Finally, overexpressing TRP-4 in specific chemosensory neurons can rescue the ultrasound-triggered behavioral deficit in the mec-4 null mutant, suggesting that these two pathways act in parallel. Together, we demonstrate that multiple mechanosensitive proteins likely cooperate to transform ultrasound stimuli into behavioral changes.

scholarly journals C. elegans synMuv B proteins regulate spatial and temporal chromatin compaction during development

2019 ◽  
Author(s):  
Meghan E. Costello ◽  
Lisa N. Petrella
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Developmental Time ◽  
Somatic Tissue ◽  
Temperature Sensitive ◽  
Germline Gene ◽  
Tissue Specific ◽  
Chromatin Compaction ◽  
C Elegans ◽  
Repressive Chromatin

AbstractTissue-specific establishment of repressive chromatin through creation of compact chromatin domains during development is necessary to ensure proper gene expression and cell fate. C. elegans synMuv B proteins are important for the soma/germline fate decision and mutants demonstrate ectopic germline gene expression in somatic tissue, especially at high temperature. We show that C. elegans synMuv B proteins regulate developmental chromatin compaction and that timing of chromatin compaction is temperature sensitive in both wild-type and synMuv B mutants. Chromatin compaction in mutants is delayed into developmental time-periods when zygotic gene expression is upregulated and demonstrates an anterior-to-posterior pattern. Loss of this patterned compaction coincides with the developmental time-period of ectopic germline gene expression that leads to a developmental arrest in synMuv B mutants. Thus, chromatin organization throughout development is regulated both spatially and temporally by synMuv B proteins to establish repressive chromatin in a tissue-specific manner to ensure proper gene expression.

scholarly journals Regulation of reproduction and longevity by nutrient-sensing pathways

2017 ◽  
Vol 217 (1) ◽  
pp. 93-106 ◽  
Author(s):  
Nicole M. Templeman ◽  
Coleen T. Murphy
Keyword(s):  
Molecular Mechanisms ◽  
Energy Levels ◽  
Somatic Growth ◽  
Reproductive Function ◽  
Adenosine Monophosphate ◽  
Somatic Tissue ◽  
Nutrient Sensing ◽  
Reproductive Capacity ◽  
Biological Processes ◽  
Signaling Systems

Nutrients are necessary for life, as they are a crucial requirement for biological processes including reproduction, somatic growth, and tissue maintenance. Therefore, signaling systems involved in detecting and interpreting nutrient or energy levels—most notably, the insulin/insulin-like growth factor 1 (IGF-1) signaling pathway, mechanistic target of rapamycin (mTOR), and adenosine monophosphate-activated protein kinase (AMPK)—play important roles in regulating physiological decisions to reproduce, grow, and age. In this review, we discuss the connections between reproductive senescence and somatic aging and give an overview of the involvement of nutrient-sensing pathways in controlling both reproductive function and lifespan. Although the molecular mechanisms that affect these processes can be influenced by distinct tissue-, temporal-, and pathway-specific signaling events, the progression of reproductive aging and somatic aging is systemically coordinated by integrated nutrient-sensing signaling pathways regulating somatic tissue maintenance in conjunction with reproductive capacity.

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