Aspartame and sucralose extend the lifespan and improve the health status of C. elegans

Quantifying cell transitions in C. elegans with data-fitted landscape models

PLoS Computational Biology ◽

10.1371/journal.pcbi.1009034 ◽

2021 ◽

Vol 17 (6) ◽

pp. e1009034

Author(s):

Elena Camacho-Aguilar ◽

Aryeh Warmflash ◽

David A. Rand

Keyword(s):

Open Problem ◽

Catastrophe Theory ◽

Approximate Bayesian Computation ◽

Underlying Mechanism ◽

Rational Method ◽

Vulval Development ◽

New Model ◽

C Elegans ◽

Landscape Models ◽

Approximate Bayesian

Increasing interest has emerged in new mathematical approaches that simplify the study of complex differentiation processes by formalizing Waddington’s landscape metaphor. However, a rational method to build these landscape models remains an open problem. Here we study vulval development in C. elegans by developing a framework based on Catastrophe Theory (CT) and approximate Bayesian computation (ABC) to build data-fitted landscape models. We first identify the candidate qualitative landscapes, and then use CT to build the simplest model consistent with the data, which we quantitatively fit using ABC. The resulting model suggests that the underlying mechanism is a quantifiable two-step decision controlled by EGF and Notch-Delta signals, where a non-vulval/vulval decision is followed by a bistable transition to the two vulval states. This new model fits a broad set of data and makes several novel predictions.

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THE ENDOPLASMIC RETICULUM PROTEIN QUALITY CONTROL ADAPTATION IN A LONG-LIVED C. ELEGANS PROTEASOMAL MUTANT

Innovation in Aging ◽

10.1093/geroni/igz038.373 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

pp. S99-S99

Author(s):

Meghna N Chinchankar ◽

Karl Rodriguez ◽

Alfred Fisher

Keyword(s):

Stress Resistance ◽

Protein Quality ◽

Underlying Mechanism ◽

26S Proteasome ◽

Protein Homeostasis ◽

Catalytic Core ◽

C Elegans ◽

Endoplasmic Reticulum Protein ◽

Extended Lifespan ◽

Er Homeostasis

Abstract Protein degradation mechanisms are integral to protein homeostasis. Their reduced efficiency during aging leads to accumulation of misfolded and aggregated proteins which potentiate proteotoxic disorders. Paradoxically, our lab reported that the Caenorhabditis elegans rpn-10(ok1865) proteasome mutant possesses enhanced proteostasis and extended lifespan. RPN-10/PSMD4 is a ubiquitin receptor of the 26S proteasome that targets polyubiquitinated substrates to its catalytic core for degradation. Proteasome dysfunction of the rpn-10 mutant is characterized by reduced, not inhibited, ubiquitin fusion degradation. We ascertained that upregulated autophagy and SKN-1/Nrf-mediated responses partially contribute to the robust rpn-10 mutant phenotype. Further investigation of its underlying mechanism revealed that several ERQC genes are transcriptionally upregulated in the rpn-10 mutant. Thus, we hypothesized that the rpn-10 mutant exhibits improved ER proteostasis which mediates its elevated cellular stress resistance. Accordingly, the rpn-10 mutant shows increased ER stress resistance and altered ER homeostasis. Complementarily, attenuated expression of the aggregation-prone α-1 antitrypsin (ATZ) reporter proves that ER proteostasis is ameliorated in the rpn-10 mutant. Via a genetic screen for suppressors of decreased ATZ aggregation in the rpn-10 mutant, we identified novel player H04D03.3, which is a homolog of the proteasome adaptor ECM29. This suggests that assembly of the rpn-10 mutant proteasome itself critically regulates its ER proteostasis. Moreover, we observed that cytosolic proteostasis and longevity depend on ER master chaperone hsp-3/-4(BiP) and ER ATPase cdc-48.2(p97/VCP), further highlighting ERQC significance in the rpn-10 mutant. Altogether, it appears that mild proteasomal dysfunction induces ERQC adaptation that underlies proteostasis and longevity benefits of the rpn-10 mutant.

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Antiaging effect of a Jianpi-yangwei formula in Caenorhabditis elegans

BMC Complementary and Alternative Medicine ◽

10.1186/s12906-019-2704-4 ◽

2019 ◽

Vol 19 (1) ◽

Author(s):

Liling Zeng ◽

Zhimin Yang ◽

Tianchan Yun ◽

Shaoyi Fan ◽

Zhong Pei ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Target Genes ◽

Underlying Mechanism ◽

Control Group ◽

Wild Type ◽

Survival Times ◽

Expression Levels ◽

C Elegans ◽

Heat Stress Resistance ◽

Increased Activity

Abstract Background Jianpi-yangwei (JPYW), a traditional Chinese medicine (TCM), helps to nourish the stomach and spleen and is primarily used to treat functional declines related to aging. This study aimed to explore the antiaging effects and mechanism of JPYW by employing a Caenorhabditis elegans model. Methods Wild-type C. elegans N2 worms were cultured in growth medium with or without JPYW, and lifespan analysis, oxidative and heat stress resistance assays, and other aging-related assays were performed. The effects of JPYW on the levels of superoxide dismutase (SOD) and the expression of specific genes were examined to explore the underlying mechanism of JPYW. Results Compared to control worms, JPYW-treated wild-type worms showed increased survival times under both normal and stress conditions (P < 0.05). JPYW-treated worms also exhibited enhanced reproduction, movement and growth and decreased intestinal lipofuscin accumulation compared to controls (P < 0.05). Furthermore, increased activity of SOD, downregulated expression levels of the proaging gene clk-2 and upregulated expression levels of the antiaging genes daf-16, skn-1, and sir-2.1 were observed in the JPYW group compared to the control group. Conclusion Our findings suggest that JPYW extends the lifespan of C. elegans and exerts antiaging effects by increasing the activity of an antioxidant enzyme (SOD) and by regulating the expression of aging-related genes. This study not only indicates that this Chinese compound exerts antiaging effects by activating and repressing target genes but also provides a proven methodology for studying the biological mechanisms of TCMs.

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Trilobatin, a Component from Lithocarpus polystachyrus Rehd., Increases Longevity in C. elegans Through Activating SKN1/SIRT3/DAF16 Signaling Pathway

Frontiers in Pharmacology ◽

10.3389/fphar.2021.655045 ◽

2021 ◽

Vol 12 ◽

Author(s):

Na Li ◽

Xi Li ◽

Yan-Ling Shi ◽

Jian-Mei Gao ◽

Yu-Qi He ◽

...

Keyword(s):

Signaling Pathway ◽

Fluorescence Intensity ◽

Body Movement ◽

Redox Homeostasis ◽

Underlying Mechanism ◽

Enhancing Effect ◽

C Elegans ◽

Beneficial Effects ◽

Oxidative Effects ◽

Effective Component

Trilobatin (TLB) is an effective component from Lithocarpus polystachyrus Rehd. Our previous study revealed that TLB protected against oxidative injury in neuronal cells by AMPK/Nrf2/SIRT3 signaling pathway. However, whether TLB can delay aging remains still a mystery. Therefore, the present study was designed to investigate the possible longevity-enhancing effect of TLB, and further to explore its underlying mechanism in Caenorhabditis elegans (C. elegans). The results showed that TLB exerted beneficial effects on C. elegans, as evidenced by survival rate, body movement assay and pharynx-pumping assay. Furthermore, TLB not only significantly decreased ROS and MDA levels, but also increased anti-oxidant enzyme activities including CAT and SOD, as well as its subtypes SOD2 andSOD3, but not affect SOD1 activity, as evidenced by heat and oxidative stress resistance assays. Whereas, the anti-oxidative effects of TLB were almost abolished in SKN1, Sir2.3, and DAF16 mutant C. elegans. Moreover, TLB augmented the fluorescence intensity of DAF16: GFP, SKN1:GFP, GST4:GFP mutants, indicating that TLB increased the contents of SKN1, SIRT3 and DAF16 due to fluorescence intensity of these mutants, which were indicative of these proteins. In addition, TLB markedly increased the protein expressions of SKN1, SIRT3 and DAF16 as evidenced by ELISA assay. However, its longevity-enhancing effect were abolished in DAF16, Sir2.3, SKN1, SOD2, SOD3, and GST4 mutant C. elegans than those of non-TLB treated controls. In conclusion, TLB effectively prolongs lifespan of C. elegans, through regulating redox homeostasis, which is, at least partially, mediated by SKN1/SIRT3/DAF16 signaling pathway.

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Quantifying cell transitions in C. elegans with data-fitted landscape models

10.1101/2021.01.22.426019 ◽

2021 ◽

Author(s):

Elena Camacho-Aguilar ◽

Aryeh Warmflash ◽

David A. Rand

Keyword(s):

Open Problem ◽

Catastrophe Theory ◽

Approximate Bayesian Computation ◽

Underlying Mechanism ◽

Rational Method ◽

Vulval Development ◽

New Model ◽

C Elegans ◽

Landscape Models ◽

Approximate Bayesian

AbstractIncreasing interest has emerged in new mathematical approaches that simplify the study of complex differentiation processes by formalizing Waddington’s landscape metaphor. However, a rational method to build these landscape models remains an open problem. Building on pioneering work by Corson and Siggia (2012, 2017) we study vulval development in C. elegans by developing a framework based on Catastrophe Theory (CT) and approximate Bayesian computation (ABC) to build data-fitted landscape models. We first identify the candidate qualitative landscapes, and then use CT to build the simplest model consistent with the data, which we quantitatively fit using ABC. The resulting model suggests that the underlying mechanism is a quantifiable two-step decision controlled by EGF and Notch-Delta signals, where a non-vulval/vulval decision is followed by a bistable transition to the two vulval states. This new model fits a broad set of data and makes several novel predictions.

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Ginsenoside Prolongs the Lifespan of C. elegans via Lipid Metabolism and Activating the Stress Response Signaling Pathway

International Journal of Molecular Sciences ◽

10.3390/ijms22189668 ◽

2021 ◽

Vol 22 (18) ◽

pp. 9668

Author(s):

Xiaoxuan Yu ◽

Hui Li ◽

Dongfa Lin ◽

Weizhuo Guo ◽

Zhihao Xu ◽

...

Keyword(s):

Lipid Metabolism ◽

Panax Ginseng ◽

Underlying Mechanism ◽

Rna Seq ◽

Ginsenoside Re ◽

Ginsenoside Rd ◽

C Elegans ◽

Kegg Pathway Analysis ◽

And Oxidative Stress ◽

Insight Into

Panax ginseng is a valuable traditional Chinese medicine in Northeast China. Ginsenoside, the active component of ginseng, has not been investigated much for its effects on aging and its underlying mechanism(s) of action. Here, we investigated the effects of total ginsenoside (TG), a mixture of the primary active ginsenosides from Panax ginseng, on the lifespan of Caenorhabditis elegans (C. elegans). We found that TG extended the lifespan of C. elegans and reduced lipofuscin accumulation. Moreover, TG increased the survival of C. elegans in response to heat and oxidative stress via the reduction of ROS. Next, we used RNA-seq to fully define the antiaging mechanism(s) of TG. The KEGG pathway analysis showed that TG can prolong the lifespan and is involved in the longevity regulating pathway. qPCR showed that TG upregulated the expression of nrh-80, daf-12, daf-16, hsf-1 and their downstream genes. TG also reduced the fat accumulation and promoted lipid metabolism. Moreover, TG failed to extend the lifespan of daf-16 and hsf-1 mutants, highlighting their role in the antiaging effects of TG in C. elegans. The four main constitution of TG were then confirmed by HPLC and included ginsenoside Re, Rg1, Rg2 and Rd. Of the ginsenosides, only ginsenoside Rd prolonged the lifespan of C. elegans to levels comparable to TG. These findings provided mechanistic insight into the antiaging effects of ginsenoside in C. elegans.

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Presenilin mutations deregulate mitochondrial Ca2+ homeostasis and metabolic activity causing neurodegeneration in Caenorhabditis elegans

eLife ◽

10.7554/elife.33052 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 25

Author(s):

Shaarika Sarasija ◽

Jocelyn T Laboy ◽

Zahra Ashkavand ◽

Jennifer Bonner ◽

Yi Tang ◽

...

Keyword(s):

Oxidative Stress ◽

Endoplasmic Reticulum ◽

Neurodegenerative Diseases ◽

Underlying Mechanism ◽

Metabolic Function ◽

Gene Encoding ◽

C Elegans ◽

Metabolic Defects ◽

Mitochondrial Superoxide ◽

Encoding Genes

Mitochondrial dysfunction and subsequent metabolic deregulation is observed in neurodegenerative diseases and aging. Mutations in the presenilin (PSEN) encoding genes (PSEN1 and PSEN2) cause most cases of familial Alzheimer’s disease (AD); however, the underlying mechanism of pathogenesis remains unclear. Here, we show that mutations in the C. elegans gene encoding a PSEN homolog, sel-12 result in mitochondrial metabolic defects that promote neurodegeneration as a result of oxidative stress. In sel-12 mutants, elevated endoplasmic reticulum (ER)-mitochondrial Ca2+ signaling leads to an increase in mitochondrial Ca2+ content which stimulates mitochondrial respiration resulting in an increase in mitochondrial superoxide production. By reducing ER Ca2+ release, mitochondrial Ca2+ uptake or mitochondrial superoxides in sel-12 mutants, we demonstrate rescue of the mitochondrial metabolic defects and prevent neurodegeneration. These data suggest that mutations in PSEN alter mitochondrial metabolic function via ER to mitochondrial Ca2+ signaling and provide insight for alternative targets for treating neurodegenerative diseases.

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Ferulic Acid Supplementation Increases Lifespan and Stress Resistance via Insulin/IGF-1 Signaling Pathway in C. elegans

International Journal of Molecular Sciences ◽

10.3390/ijms22084279 ◽

2021 ◽

Vol 22 (8) ◽

pp. 4279

Author(s):

Hui Li ◽

Xiaoxuan Yu ◽

Fanwei Meng ◽

Zhenyu Zhao ◽

Shuwen Guan ◽

...

Keyword(s):

Ferulic Acid ◽

Signaling Pathway ◽

Underlying Mechanism ◽

Free Radical Scavenger ◽

Radical Scavenger ◽

Lifespan Extension ◽

Rna Seq ◽

E Coli ◽

C Elegans ◽

Mitochondrial Signaling

Ferulic acid (FA) is a naturally-occurring well-known potent antioxidant and free radical scavenger. FA supplementation is an effective strategy to delay aging, but the underlying mechanism remains unknown. In the present study, we examined the effects of FA on lifespan extension and its mechanism of FA in Caenorhabditis elegans (C. elegans). Results suggested that FA increased the lifespan of C. elegans, rather than altering the growth of E. coli OP50. Meanwhile, FA promoted the healthspan of C. elegans by improving locomotion and reducing fat accumulation and polyQ aggregation. FA increased the resistance to heat and oxidative stress through reducing ROS. The upregulating of the expression of the hlh-30, skn-1, and hsf-1 were involved in the FA-mediated lifespan extension. Furthermore, FA treatment had no impact on the lifespan of daf-2, hlh-30, skn-1, and hsf-1 mutants, confirming that insulin/IGF-1 signaling pathway and multiple longevity mechanisms were associated with the longevity mechanism of FA. We further found that mitochondrial signaling pathway was modulation involved in FA-mediated lifespan extension. With the results from RNA-seq results and mutants lifespan assay. These findings contribute to our knowledge of the lifespan extension and underlying mechanism of action of FA in C. elegans.

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H3K9me1/2 methylation limits the lifespan of C. elegans

10.1101/2021.10.27.466082 ◽

2021 ◽

Author(s):

Shouhong Guang ◽

Meng Huang ◽

Minjie Hong ◽

Chengming Zhu ◽

Di Chen ◽

...

Keyword(s):

Histone Methylation ◽

Molecular Mechanisms ◽

Target Genes ◽

Underlying Mechanism ◽

Lifespan Extension ◽

Mrna Levels ◽

C Elegans ◽

Histone 3 ◽

Stem Cell Pluripotency ◽

Receptor Mutant

Histone methylation plays crucial roles in the development, gene regulation and maintenance of stem cell pluripotency in mammals. Recent work shows that histone methylation is associated with aging, yet the underlying mechanism remains unclear. In this work, we identified a class of histone 3 lysine 9 mono-/dimethyltransferase genes (met-2, set-6, set-19, set-20, set-21, set-32 and set-33), mutations in which induce synergistic lifespan extension in the long-lived DAF-2 (IGF-1 receptor) mutant in C. elegans. These histone methyltransferase plus daf-2 double mutants not only exhibited an average lifespan nearly three times that of wild-type animals and a maximal lifespan of approximately 100 days, but also significantly increased resistance to oxidative and heat stress. Synergistic lifespan extension depends on the transcription factor DAF-16 (FOXO). mRNA-seq experiments revealed that the mRNA levels of class I DAF-16 target genes, which are activated by DAF-16, were further elevated in the double mutants. Among these genes, F35E8.7, nhr-62, sod-3, asm-2 and Y39G8B.7 are required for the lifespan extension of the daf-2;set-21 double mutant. In addition, treating daf-2 animals with the H3K9me1/2 methyltransferase G9a inhibitor also extends lifespan and increases stress resistance. Therefore, investigation of DAF-2 and H3K9me1/2 methyltransferase deficiency-mediated synergistic longevity will contribute to a better understanding of the molecular mechanisms of aging and therapeutic applications.

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The Toxicity Assessment of ethyl p-hydroxybenzoate in Nematode C. elegans

International Journal of Biology ◽

10.5539/ijb.v8n3p38 ◽

2016 ◽

Vol 8 (3) ◽

pp. 38 ◽

Cited By ~ 2

Author(s):

Ting Xue ◽

Linsong Yang

Keyword(s):

Adverse Effect ◽

Prolonged Exposure ◽

Low Cost ◽

Underlying Mechanism ◽

Toxicity Assessment ◽

Human Reproduction ◽

C Elegans ◽

Reproduction System ◽

Locomotion Behavior ◽

Underlying Mechanisms

Ethyl paraben (EP) is an antiseptic commonly used in food, medicine, cosmetics, and children's products. Parabens are popular due to their broad antibacterial spectrum, low cost, and stable pH characteristics, and though once considered safe as well as effective, recent studies have shown that EP has considerable oestrogenic activity which has adverse effect on the human reproduction system. In our study, we used a Caenorhabditis elegans assay system to investigate EP toxicity and its underlying mechanism. We found that prolonged exposure to EP decreased body length and locomotion behavior in the nematodes. Furthermore, most of the toxicities were transferable. Locomotion behavior defects were only partially recovered in progeny, and higher concentrations caused more significant defects; locomotion behavior improved after subsequent exposure to mutants PMK-1 and PMK-3. Taken together, the results showed that EP exerts adverse effect on C. elegans and may induce toxicity through various underlying mechanisms.

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