scholarly journals A ROBOTIC SYSTEM FOR HIGH-THROUGHPUT AUTOMATED LIFESPAN ANALYSIS IN C. ELEGANS

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S102-S102
Author(s):  
Ben Blue ◽  
Elena Vayndorf ◽  
Matt Kaeberlein ◽  
Jason Pitt
Keyword(s):  
High Throughput ◽  
Digital Camera ◽  
Nematode Species ◽  
Time Lapse ◽  
Small Population ◽  
Robotic System ◽  
Model Organisms ◽  
C Elegans ◽  
Age Related ◽  
Short Video

Abstract Over the past decade, the identification of potential genetic and pharmacological modifiers of lifespan and age-related pathologies in C. elegans and other model organisms has yielded fruitful leads for follow-up investigation. A major limitation of such studies, however, is that they are often time-consuming and labor-intensive. The advent of affordable high-quality digital cameras, robotics systems, and 3D printers, as well as the decreasing costs of image storage and processing have allowed us to automate data capture and analysis at an unprecedented scale. To this end, our group developed a tool consisting of an unbiased, high-throughput, automated robotic system to perform genetic and pharmacological quantification of lifespan and health measures in C. elegans and related nematode species. The WormBot utilizes industry-standard, commercially available robotics components to position a digital camera over individual wells of standard 12-well culture plates, containing a small population of C. elegans per well. A high-resolution image is captured of each plate every 10 minutes throughout the course of the experiment. Our software processes the images for stabilization, compiles them into a time-lapse series for each well, and quantifies survival and mobility (paralysis) with minimal input. In addition, a short video is captured of each well once each day, to allow for quantitative analyses of activity and coordinated movement. We will describe this technology and present applications to screen genetic and pharmacological libraries in aging and age-related disease.

scholarly journals A robotic system for high-throughput automated lifespan and phenotyping analysis in C. elegans

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 886-886
Author(s):  
Elena Vayndorf ◽  
Jason Pitt ◽  
Judy Wu ◽  
Emily Chang ◽  
Richard Nguyen ◽  
...  
Keyword(s):  
High Throughput ◽  
Large Scale ◽  
Nematode Species ◽  
Robotic System ◽  
Model Organisms ◽  
Biological Aging ◽  
Digital Cameras ◽  
C Elegans ◽  
Age Related ◽  
3D Printers

Abstract A goal of gerontology-related research is to develop therapies to improve the healthy period of life by understanding and targeting the molecular hallmarks of biological aging. Much progress has been made toward understanding the genetic and biochemical nature of these hallmarks through studies using simple invertebrate model organisms, such as the nematode Caenorhabditis elegans. Over the past decade, the identification of potential genetic and pharmacological modifiers of lifespan and age-related pathologies in C. elegans and other model organisms has yielded fruitful leads for follow-up investigation. However, such studies are typically time- consuming and labor-intensive. The goal of our work is to automate tasks that require frequent, repeated observations and hours of manual labor to collect and analyze lifespan, motility, and other behavioral data in C. elegans and other nematode models. The advent of affordable high-quality digital cameras, robotics systems, and 3D printers, as well as the decreasing financial and computational costs of image storage and processing, have allowed us to automate data capture and analysis on a large scale. To this end, our group recently developed a tool, we call the WormBot, consisting of an unbiased, high-throughput, automated robotic system and corresponding software, to perform genetic and pharmacological quantification of lifespan and health measures in C. elegans and related nematode species. We will report updates recently made to this system, including significant improvements to hardware, and present screening results from proteasome stimulator drugs known to reduce the accumulation of proteotoxic proteins linked to neurodegenerative diseases and aging.

scholarly journals Phenotypic Screening in C. elegans as a Tool for the Discovery of New Geroprotective Drugs

2020 ◽  
Vol 13 (8) ◽  
pp. 164 ◽  
Author(s):  
Sven Bulterijs ◽  
Bart P. Braeckman
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Aging Process ◽  
Population Aging ◽  
Model Organisms ◽  
Pharmacological Interventions ◽  
C Elegans ◽  
System A ◽  
Age Related ◽  
Screening Strategies

Population aging is one of the largest challenges of the 21st century. As more people live to advanced ages, the prevalence of age-related diseases and disabilities will increase placing an ever larger burden on our healthcare system. A potential solution to this conundrum is to develop treatments that prevent, delay or reduce the severity of age-related diseases by decreasing the rate of the aging process. This ambition has been accomplished in model organisms through dietary, genetic and pharmacological interventions. The pharmacological approaches hold the greatest opportunity for successful translation to the clinic. The discovery of such pharmacological interventions in aging requires high-throughput screening strategies. However, the majority of screens performed for geroprotective drugs in C. elegans so far are rather low throughput. Therefore, the development of high-throughput screening strategies is of utmost importance.

scholarly journals An economical and highly adaptable optogenetics system for individual and population-level manipulation of Caenorhabditis elegans

BMC Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
M. Koopman ◽  
L. Janssen ◽  
E. A. A. Nollen
Keyword(s):  
Caenorhabditis Elegans ◽  
Light Stimulus ◽  
Cholinergic Neurons ◽  
Model Organisms ◽  
Parameter Study ◽  
Multiple Model ◽  
Excitable Cells ◽  
Specific Expression ◽  
C Elegans ◽  
Age Related

Abstract Background Optogenetics allows the experimental manipulation of excitable cells by a light stimulus without the need for technically challenging and invasive procedures. The high degree of spatial, temporal, and intensity control that can be achieved with a light stimulus, combined with cell type-specific expression of light-sensitive ion channels, enables highly specific and precise stimulation of excitable cells. Optogenetic tools have therefore revolutionized the study of neuronal circuits in a number of models, including Caenorhabditis elegans. Despite the existence of several optogenetic systems that allow spatial and temporal photoactivation of light-sensitive actuators in C. elegans, their high costs and low flexibility have limited wide access to optogenetics. Here, we developed an inexpensive, easy-to-build, modular, and adjustable optogenetics device for use on different microscopes and worm trackers, which we called the OptoArm. Results The OptoArm allows for single- and multiple-worm illumination and is adaptable in terms of light intensity, lighting profiles, and light color. We demonstrate OptoArm’s power in a population-based multi-parameter study on the contributions of motor circuit cells to age-related motility decline. We found that individual components of the neuromuscular system display different rates of age-dependent deterioration. The functional decline of cholinergic neurons mirrors motor decline, while GABAergic neurons and muscle cells are relatively age-resilient, suggesting that rate-limiting cells exist and determine neuronal circuit ageing. Conclusion We have assembled an economical, reliable, and highly adaptable optogenetics system which can be deployed to address diverse biological questions. We provide a detailed description of the construction as well as technical and biological validation of our set-up. Importantly, use of the OptoArm is not limited to C. elegans and may benefit studies in multiple model organisms, making optogenetics more accessible to the broader research community.

scholarly journals Youthful and age-related matreotypes predict drugs promoting longevity

2021 ◽  
Author(s):  
Cyril Statzer ◽  
Elisabeth Jongsma ◽  
Sean X. Liu ◽  
Alexander Dakhovnik ◽  
Franziska Wandrey ◽  
...  
Keyword(s):  
Gene Expression ◽  
Extracellular Matrix ◽  
Gene Expression Pattern ◽  
Surrogate Marker ◽  
Model Organisms ◽  
List Type ◽  
C Elegans ◽  
Drug Candidates ◽  
Matrix Gene ◽  
Age Related

AbstractThe identification and validation of drugs that promote health during aging (‘geroprotectors’) is key to the retardation or prevention of chronic age-related diseases. Here we found that most of the established pro-longevity compounds shown to extend lifespan in model organisms also alter extracellular matrix gene expression (i.e., matrisome) in human cell lines. To harness this novel observation, we used age-stratified human transcriptomes to define the age-related matreotype, which represents the matrisome gene expression pattern associated with age. Using a ‘youthful’ matreotype, we screened in silico for geroprotective drug candidates. To validate drug candidates, we developed a novel tool using prolonged collagen expression as a non-invasive and in-vivo surrogate marker for C. elegans longevity. With this reporter, we were able to eliminate false positive drug candidates and determine the appropriate dose for extending the lifespan of C. elegans. We improved drug uptake for one of our predicted compounds, genistein, and reconciled previous contradictory reports of its effects on longevity. We identified and validated new compounds, tretinoin, chondroitin sulfate, and hyaluronic acid, for their ability to restore age-related decline of collagen homeostasis and increase lifespan. Thus, our innovative drug screening approach - employing extracellular matrix homeostasis - facilitates the discovery of pharmacological interventions promoting healthy aging.HighlightsMany geroprotective drugs alter extracellular matrix gene expressionDefined young and old human matreotype signatures can identify novel potential geroprotective compoundsProlonged collagen homeostasis as a surrogate marker for longevity

scholarly journals Drug Screening Implicates Chondroitin Sulfate as a Potential Longevity Pill

2021 ◽  
Vol 2 ◽  
Author(s):  
Collin Y. Ewald
Keyword(s):  
Extracellular Matrix ◽  
Chondroitin Sulfate ◽  
Randomized Clinical Trials ◽  
Matrix Proteins ◽  
Model Organisms ◽  
Human Longevity ◽  
Healthy Human ◽  
Oral Supplementation ◽  
C Elegans ◽  
Age Related

Discovering compounds that promote health during aging (“geroprotectors”) is key to the retardation of age-related pathologies and the prevention of chronic age-related diseases. In in-silico and model organisms’ lifespan screens, chondroitin sulfate has emerged as a geroprotective compound. Chondroitin sulfate is a glycosaminoglycan attached to extracellular matrix proteins and is naturally produced by our body. Oral supplementation of chondroitin sulfate shows a high tolerance in humans, preferable pharmacokinetics, a positive correlation with healthy human longevity, and efficacy in deceleration of age-related diseases in randomized clinical trials. We have recently shown that chondroitin sulfate supplementation increases the lifespan of C. elegans. Thus, chondroitin sulfate holds the potential to become a geroprotective strategy to promote health during human aging. This review discusses the two major potential mechanisms of action, extracellular matrix homeostasis and inhibition of inflammation, that counteract age-related pathologies upon chondroitin sulfate supplementation.

scholarly journals Glucose increases the lifespan of post-reproductive C. elegans independently of FOXO

2018 ◽  
Author(s):  
Wang Lei ◽  
Caroline Beaudoin-Chabot ◽  
Guillaume Thibault
Keyword(s):  
Er Stress ◽  
Stress Resistance ◽  
Metabolic Diseases ◽  
Strong Association ◽  
Cellular Damage ◽  
Model Organisms ◽  
Dependent Manner ◽  
C Elegans ◽  
Age Related ◽  
Er Homeostasis

ABSTRACTAging is one of the most critical risk factors for the development of metabolic syndromes1. Prominent metabolic diseases, namely type 2 diabetes and insulin resistance, have a strong association with endoplasmic reticulum (ER) stress2. Upon ER stress, the unfolded protein response (UPR) is activated to limit cellular damage by adapting to stress conditions and restoring ER homeostasis3,4. However, adaptive genes upregulated from the UPR tend to decrease with age5. Although stress resistance correlates with increased longevity in a variety of model organisms, the links between the UPR, ER stress resistance, and longevity remain poorly understood. Here, we show that supplementing bacteria diet with 2% glucose (high glucose diet, HGD) in post-reproductive 7-day-old (7DO) C. elegans significantly extend their lifespan in contrast to shortening the lifespan of reproductive 3-day-old (3DO) animals. The insulin-IGF receptor DAF-2 and its immediate downstream target, phosphoinositide 3-kinase (PI3K) AGE-1, were found to be critical factors in extending the lifespan of 7DO worms on HGD. The downstream transcription factor forkhead box O (FOXO) DAF-16 did not extend the lifespan of 7DO worms on HGD in contrast of its previously reported role in modulating lifespan of 3DO worms6. Furthermore, we identified that UPR activation through the highly conserved ATF-6 and PEK-1 sensors significantly extended the longevity of 7DO worms on HGD but not through the IRE-1 sensor. Our results demonstrate that HGD extends lifespan of post-reproductive worms in a UPR-dependent manner but independently of FOXO. Based on these observations, we hypothesise that HGD activates the otherwise quiescent UPR in aged worms to overcome age-related stress and to restore ER homeostasis. In contrast, young adult animals subjected to HGD leads to unresolved ER stress, conversely leading to a deleterious stress response.

The glycomes of Caenorhabditis elegans and other model organisms

2002 ◽  
Vol 69 ◽  
pp. 117-134 ◽  
Author(s):  
Stuart M. Haslam ◽  
David Gems ◽  
Howard R. Morris ◽  
Anne Dell
Keyword(s):  
Caenorhabditis Elegans ◽  
Current Knowledge ◽  
Structural Data ◽  
Model Organisms ◽  
Entire Genome ◽  
C Elegans ◽  
The Face ◽  
Area Of Concern ◽  
Nematode Worm

There is no doubt that the immense amount of information that is being generated by the initial sequencing and secondary interrogation of various genomes will change the face of glycobiological research. However, a major area of concern is that detailed structural knowledge of the ultimate products of genes that are identified as being involved in glycoconjugate biosynthesis is still limited. This is illustrated clearly by the nematode worm Caenorhabditis elegans, which was the first multicellular organism to have its entire genome sequenced. To date, only limited structural data on the glycosylated molecules of this organism have been reported. Our laboratory is addressing this problem by performing detailed MS structural characterization of the N-linked glycans of C. elegans; high-mannose structures dominate, with only minor amounts of complex-type structures. Novel, highly fucosylated truncated structures are also present which are difucosylated on the proximal N-acetylglucosamine of the chitobiose core as well as containing unusual Fucα1–2Gal1–2Man as peripheral structures. The implications of these results in terms of the identification of ligands for genomically predicted lectins and potential glycosyltransferases are discussed in this chapter. Current knowledge on the glycomes of other model organisms such as Dictyostelium discoideum, Saccharomyces cerevisiae and Drosophila melanogaster is also discussed briefly.

scholarly journals Two human metabolites rescue a C. elegans model of Alzheimer’s disease via a cytosolic unfolded protein response

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Priyanka Joshi ◽  
Michele Perni ◽  
Ryan Limbocker ◽  
Benedetta Mannini ◽  
Sam Casford ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Unfolded Protein Response ◽  
Neurodegenerative Disorders ◽  
C Elegans ◽  
Unfolded Protein ◽  
Model Of Alzheimer’S Disease ◽  
Age Related ◽  
Parkinson’S Diseases ◽  
Protein Response

AbstractAge-related changes in cellular metabolism can affect brain homeostasis, creating conditions that are permissive to the onset and progression of neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. Although the roles of metabolites have been extensively studied with regard to cellular signaling pathways, their effects on protein aggregation remain relatively unexplored. By computationally analysing the Human Metabolome Database, we identified two endogenous metabolites, carnosine and kynurenic acid, that inhibit the aggregation of the amyloid beta peptide (Aβ) and rescue a C. elegans model of Alzheimer’s disease. We found that these metabolites act by triggering a cytosolic unfolded protein response through the transcription factor HSF-1 and downstream chaperones HSP40/J-proteins DNJ-12 and DNJ-19. These results help rationalise previous observations regarding the possible anti-ageing benefits of these metabolites by providing a mechanism for their action. Taken together, our findings provide a link between metabolite homeostasis and protein homeostasis, which could inspire preventative interventions against neurodegenerative disorders.

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