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

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.

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

Innovation in Aging ◽

10.1093/geroni/igaa057.3270 ◽

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.

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

Innovation in Aging ◽

10.1093/geroni/igz038.383 ◽

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.

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Omics in a Digital World: The Role of Bioinformatics in Providing New Insights Into Human Aging

Frontiers in Genetics ◽

10.3389/fgene.2021.689824 ◽

2021 ◽

Vol 12 ◽

Author(s):

Serena Dato ◽

Paolina Crocco ◽

Nicola Rambaldi Migliore ◽

Francesco Lescai

Keyword(s):

High Throughput ◽

Aging Process ◽

Single Cell Analysis ◽

Physiological Age ◽

Data Types ◽

Aging Research ◽

Digital World ◽

Age Related ◽

Critical Issues ◽

The Individual

BackgroundAging is a complex phenotype influenced by a combination of genetic and environmental factors. Although many studies addressed its cellular and physiological age-related changes, the molecular causes of aging remain undetermined. Considering the biological complexity and heterogeneity of the aging process, it is now clear that full understanding of mechanisms underlying aging can only be achieved through the integration of different data types and sources, and with new computational methods capable to achieve such integration.Recent AdvancesIn this review, we show that an omics vision of the age-dependent changes occurring as the individual ages can provide researchers with new opportunities to understand the mechanisms of aging. Combining results from single-cell analysis with systems biology tools would allow building interaction networks and investigate how these networks are perturbed during aging and disease. The development of high-throughput technologies such as next-generation sequencing, proteomics, metabolomics, able to investigate different biological markers and to monitor them simultaneously during the aging process with high accuracy and specificity, represents a unique opportunity offered to biogerontologists today.Critical IssuesAlthough the capacity to produce big data drastically increased over the years, integration, interpretation and sharing of high-throughput data remain major challenges. In this paper we present a survey of the emerging omics approaches in aging research and provide a large collection of datasets and databases as a useful resource for the scientific community to identify causes of aging. We discuss their peculiarities, emphasizing the need for the development of methods focused on the integration of different data types.Future DirectionsWe critically review the contribution of bioinformatics into the omics of aging research, and we propose a few recommendations to boost collaborations and produce new insights. We believe that significant advancements can be achieved by following major developments in bioinformatics, investing in diversity, data sharing and community-driven portable bioinformatics methods. We also argue in favor of more engagement and participation, and we highlight the benefits of new collaborations along these lines. This review aims at being a useful resource for many researchers in the field, and a call for new partnerships in aging research.

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Biological Age Prediction From Wearable Device Movement Data Identifies Nutritional and Pharmacological Interventions for Healthy Aging

Frontiers in Aging ◽

10.3389/fragi.2021.708680 ◽

2021 ◽

Vol 2 ◽

Author(s):

Rebecca L. McIntyre ◽

Mizanur Rahman ◽

Siva A. Vanapalli ◽

Riekelt H. Houtkooper ◽

Georges E. Janssens

Keyword(s):

Healthy Aging ◽

Machine Learning Algorithms ◽

Biological Age ◽

Wearable Device ◽

Biological Aging ◽

Accelerometer Data ◽

Pharmacological Interventions ◽

C Elegans ◽

Movement Data ◽

Age Related

Intervening in aging processes is hypothesized to extend healthy years of life and treat age-related disease, thereby providing great benefit to society. However, the ability to measure the biological aging process in individuals, which is necessary to test for efficacy of these interventions, remains largely inaccessible to the general public. Here we used NHANES physical activity accelerometer data from a wearable device and machine-learning algorithms to derive biological age predictions for individuals based on their movement patterns. We found that accelerated biological aging from our “MoveAge” predictor is associated with higher all-cause mortality. We further searched for nutritional or pharmacological compounds that associate with decelerated aging according to our model. A number of nutritional components peak in their association to decelerated aging later in life, including fiber, magnesium, and vitamin E. We additionally identified one FDA-approved drug associated with decelerated biological aging: the alpha-blocker doxazosin. We show that doxazosin extends healthspan and lifespan in C. elegans. Our work demonstrates how a biological aging score based on relative mobility can be accessible to the wider public and can potentially be used to identify and determine efficacy of geroprotective interventions.

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High‐Throughput Screening for Novel Anti‐Infectives Using a C. elegans Pathogenesis Model

Current Protocols in Chemical Biology ◽

10.1002/9780470559277.ch130160 ◽

2014 ◽

Vol 6 (1) ◽

pp. 25-37 ◽

Cited By ~ 30

Author(s):

Annie L. Conery ◽

Jonah Larkins‐Ford ◽

Frederick M. Ausubel ◽

Natalia V. Kirienko

Keyword(s):

High Throughput ◽

High Throughput Screening ◽

C Elegans

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A High-Throughput Cellular Screening Assay for Small-Molecule Inhibitors and Activators of Cytoplasmic Dynein-1-Based Cargo Transport

SLAS DISCOVERY Advancing Life Sciences ◽

10.1177/2472555220920581 ◽

2020 ◽

Vol 25 (9) ◽

pp. 985-999

Author(s):

John Vincent ◽

Marian Preston ◽

Elizabeth Mouchet ◽

Nicolas Laugier ◽

Adam Corrigan ◽

...

Keyword(s):

Small Molecule ◽

High Throughput ◽

High Throughput Screening ◽

Small Molecule Inhibitors ◽

Cytoplasmic Dynein ◽

Lead Discovery ◽

Screening Assay ◽

Age Related ◽

The Uk

Cytoplasmic dynein-1 (hereafter dynein) is a six-subunit motor complex that transports a variety of cellular components and pathogens along microtubules. Dynein’s cellular functions are only partially understood, and potent and specific small-molecule inhibitors and activators of this motor would be valuable for addressing this issue. It has also been hypothesized that an inhibitor of dynein-based transport could be used in antiviral or antimitotic therapy, whereas an activator could alleviate age-related neurodegenerative diseases by enhancing microtubule-based transport in axons. Here, we present the first high-throughput screening (HTS) assay capable of identifying both activators and inhibitors of dynein-based transport. This project is also the first collaborative screening report from the Medical Research Council and AstraZeneca agreement to form the UK Centre for Lead Discovery. A cellular imaging assay was used, involving chemically controlled recruitment of activated dynein complexes to peroxisomes. Such a system has the potential to identify molecules that affect multiple aspects of dynein biology in vivo. Following optimization of key parameters, the assay was developed in a 384-well format with semiautomated liquid handling and image acquisition. Testing of more than 500,000 compounds identified both inhibitors and activators of dynein-based transport in multiple chemical series. Additional analysis indicated that many of the identified compounds do not affect the integrity of the microtubule cytoskeleton and are therefore candidates to directly target the transport machinery.

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High throughput screening strategies and technology platforms for detection of pathogens

High Throughput Screening for Food Safety Assessment ◽

10.1016/b978-0-85709-801-6.00001-0 ◽

2015 ◽

pp. 1-9

Author(s):

A.K. Bhunia ◽

C.R. Taitt ◽

M.S. Kim

Keyword(s):

High Throughput ◽

High Throughput Screening ◽

Technology Platforms ◽

Screening Strategies

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Effects of Lycium barbarum Polysaccharides on Health and Aging of C. elegans Depend on daf-12/daf-16

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/6379493 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14 ◽

Cited By ~ 1

Author(s):

Zhaokang Zhang ◽

Yannan Zhou ◽

Haitao Fan ◽

Kirunda John Billy ◽

Yunjie Zhao ◽

...

Keyword(s):

Mrna Expression ◽

Aging Process ◽

Functional Foods ◽

Mrna Expression Level ◽

Lycium Barbarum ◽

C Elegans ◽

Age Related ◽

Aging And Health ◽

Global Population ◽

Lycium Barbarum Polysaccharides

As the global population ages, searching for drugs and functional foods which can slow down the aging process has attracted a number of researchers. In this paper, the Lycium barbarum polysaccharides (LBP) extracted from Lycium barbarum was characterized and the effects of LBP on the aging and health of C. elegans were studied. Results showed that LBP can prolong the lifespan, improve the abilities to withstand environmental stress, enhance reproductive potentials, and maintain muscle integrity of C. elegans. By using genetically mutated C. elegans strains, RNAi gene silencing, and measuring the mRNA expression level, it was demonstrated that the lifespan of C. elegans was extended by LBP mainly through sir-2.1, daf-12, and daf-16. The present study might provide a basis for further study of LBP as a food or drug to interfere with aging and reduce the incidence of age-related diseases.

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