Drug Screening Implicates Chondroitin Sulfate as a Potential Longevity Pill

Frontiers in Aging ◽

10.3389/fragi.2021.741843 ◽

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.

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Youthful and age-related matreotypes predict drugs promoting longevity

10.1101/2021.01.26.428242 ◽

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

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A transient apical extracellular matrix relays cytoskeletal patterns to shape permanent acellular ridges on the surface of adult C. elegans

10.1101/2021.12.28.474392 ◽

2021 ◽

Author(s):

Sophie S. Katz ◽

Trevor J. Barker ◽

Hannah M. Maul-Newby ◽

Alessandro P. Sparacio ◽

Ken C.Q. Nguyen ◽

...

Keyword(s):

Extracellular Matrix ◽

Actin Filaments ◽

Matrix Proteins ◽

Extracellular Matrices ◽

Matrix Structure ◽

Cortical Actin ◽

Acellular Matrix ◽

C Elegans ◽

Matrix Layer ◽

Set Up

Apical extracellular matrices can form protruding structures such as denticles, ridges, scales, or teeth on the surfaces of epithelia. The mechanisms that shape these structures remain poorly understood. Here, we show how the actin cytoskeleton and a provisional matrix work together to sculpt acellular longitudinal alae ridges in the cuticle of adult C. elegans. Transient actomyosin-dependent constriction of the underlying lateral epidermis accompanies deposition of the provisional matrix at the earliest stages of alae formation. Actin is required to pattern the provisional matrix into longitudinal bands that are initially offset from the pattern of longitudinal actin filaments. These bands appear ultrastructurally as alternating regions of adhesion and separation within laminated provisional matrix layers. The provisional matrix is required to establish these demarcated zones of adhesion and separation, which ultimately give rise to alae ridges and their intervening valleys, respectively. Provisional matrix proteins shape the alae ridges and valleys but are not present within the final structure. We propose a morphogenetic mechanism wherein cortical actin patterns are relayed mechanically to the laminated provisional matrix to set up distinct zones of matrix layer separation and accretion that shape a permanent and acellular matrix structure.

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

BMC Biology ◽

10.1186/s12915-021-01085-2 ◽

2021 ◽

Vol 19 (1) ◽

Cited By ~ 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.

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Receptor-mediated adhesive and anti-adhesive functions of chondroitin sulfate proteoglycan preparations from embryonic chicken brain

Journal of Cell Science ◽

10.1242/jcs.108.12.3807 ◽

1995 ◽

Vol 108 (12) ◽

pp. 3807-3816 ◽

Cited By ~ 1

Author(s):

H. Ernst ◽

M.K. Zanin ◽

D. Everman ◽

S. Hoffman

Keyword(s):

Extracellular Matrix ◽

Chondroitin Sulfate ◽

Cell Attachment ◽

Extracellular Matrix Proteins ◽

Cell Spreading ◽

The Other ◽

Matrix Proteins ◽

Surface Receptors ◽

Core Proteins ◽

Proteoglycan Aggregates

Chondroitin sulfate proteoglycans inhibit the adhesion of cells to extracellular matrix proteins that otherwise permit adhesion. Although proteoglycans are widely assumed to act by masking the other protein in a mixed substrate, recent studies suggest that proteoglycans inhibit adhesion through mechanisms initiated by their binding to specific cell surface receptors. To explore this issue, we developed a purification scheme to isolate proteoglycan aggregates, monomers, and core proteins. Two distinct adhesion assays were used to study the interaction of these proteoglycan preparations with human foreskin fibroblasts: the gravity assay in which cell attachment is stabilized by cell spreading, and the centrifugation assay in which spreading does not play a role. All proteoglycan preparations mediate adhesion in the centrifugation assay but not in the gravity assay. In the centrifugation assay, proteoglycan aggregates and monomers are considerably more active than other extracellular matrix proteins while proteoglycan core proteins are at least as active as other extracellular matrix proteins. Proteoglycan core proteins bind to cell-associated hyaluronic acid, but not to integrins. Using mixed substrates in the gravity assay, all proteoglycan preparations inhibited cell attachment to fibronectin and vitronectin but not to collagen I and laminin. Although proteoglycan aggregates and monomers are more active than core proteins in inhibiting adhesion in the gravity assay, core proteins are still clearly active. A variety of control experiments suggest that the inhibition of cell attachment by proteoglycans is mediated through the specific interactions of proteoglycans with cell surface receptors, resulting in the inhibition of cell spreading. These results suggest at least two molecular mechanisms for proteoglycan-fibroblast interactions, one involving the chondroitin sulfate on the proteoglycan and an as yet unidentified receptor, the other involving the proteoglycan core protein and cell-associated hyaluronic acid.

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Age-related changes of DRG neuronal attachment to extracellular matrix proteins in vitro

Neuroreport ◽

10.1097/00001756-199306000-00015 ◽

1993 ◽

Vol 4 (6) ◽

pp. 663-666 ◽

Cited By ~ 8

Author(s):

Kazunori Sango ◽

Hidenori Horie ◽

Shuji Inoue ◽

Yutaro Takamura ◽

Toshifumi Takenaka

Keyword(s):

Extracellular Matrix ◽

Extracellular Matrix Proteins ◽

Matrix Proteins ◽

Age Related ◽

Age Related Changes

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

Pharmaceuticals ◽

10.3390/ph13080164 ◽

2020 ◽

Vol 13 (8) ◽

pp. 164 ◽

Cited By ~ 1

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.

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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 novel approach of human geroprotector discovery by targeting the converging subnetworks of aging and age-related diseases

10.1101/326264 ◽

2018 ◽

Author(s):

Jialiang Yang ◽

Bin Zhang ◽

Sander Houten ◽

Eric Schadt ◽

Jun Zhu ◽

...

Keyword(s):

Model Organisms ◽

Human Longevity ◽

Effective Interventions ◽

Age Related ◽

Novel Approach ◽

Transcriptional Changes ◽

Speed Up ◽

Genetic Interventions ◽

Novel Strategy

AbstractA key goal of geroscience research is to discover effective interventions to extend human healthspan, the years of healthy life. Currently, majority of the geroprotectors are found by testing compounds in model organisms; whether these compounds will be effective in humans is largely unknown. Here we present a novel strategy called ANDRU (aging network based drug discovery) to help the discovery of human geroprotectors. Instead of relying on model organisms, this approach is driven by human genomic and pharmacogenomic data. It first identifies human aging subnetworks that putatively function at the interface between aging and age-related diseases; it then screens for pharmacological or genetic interventions that may “reverse” the age-associated transcriptional changes seen in these subnetworks. We applied ANDRU to human adipose and artery tissues. In adipose tissue, PTPN1, a target for diabetes treatment and APOE, a known genetic factor for human longevity and diseases like Alzheimer’s disease, were ranked at the top. For small molecules, conjugated linoleic acid and metformin, a drug commonly used to treat type 2 diabetes, were ranked among the top compounds. In artery tissue, N-methyl-D-aspartate antagonists and curcumin were ranked at the top. In summary, ANDRU represents a promising human data-driven strategy that may speed up the discovery of interventions to extend human healthspan.

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THE LONGEVITY CONSORTIUM VISION

Innovation in Aging ◽

10.1093/geroni/igz038.758 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

pp. S208-S209

Author(s):

Daniel S Evans ◽

Steven R Cummings ◽

Nicholas Schork

Keyword(s):

Healthy Aging ◽

Human Longevity ◽

Cooperative Research ◽

Healthy Human ◽

Molecular Features ◽

Human Lifespan ◽

Age Related ◽

Show Evidence ◽

Funding Opportunities ◽

Multiple Chronic Diseases

Abstract Molecular factors and pathways promoting human longevity and healthy aging can potentially delay or prevent multiple chronic diseases and conditions, but identifying such factors that can be pharmacologically targeted requires an integrated multidisciplinary approach. We describe the design of the five research projects and three cores of the Longevity Consortium (LC) and how their cooperative research is designed to discover molecular factors and pathways that can predict healthy human aging and longevity, associate with extreme human lifespan, show relevance to chronic age-related conditions, respond to interventions to slow aging in mice, and show evidence for association with lifespan across species. A systems biology approach is undertaken to identify common molecular features across human traits and organisms, and a chemoinformatics approach to link molecular targets to candidate healthy aging interventions. The LC results are made publicly available and we provide funding opportunities to the scientific community to support pilot projects.

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