Youthful and age-related matreotypes predict drugs promoting longevity

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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Pharmacological inhibition of longevity regulator PAPP-A restrains mesenchymal stromal cell activity

10.1101/2020.02.05.936310 ◽

2020 ◽

Author(s):

Mary Mohrin ◽

Justin Liu ◽

Jose Zavala-Solorio ◽

Sakshi Bhargava ◽

John Maxwell Trumble ◽

...

Keyword(s):

Gene Expression ◽

Bone Marrow ◽

Extracellular Matrix ◽

Mesenchymal Stromal Cell ◽

Stromal Cell ◽

Cell Activity ◽

Short Term Treatment ◽

Matrix Gene ◽

Age Related ◽

Igf Signaling

AbstractReducing insulin-like growth factor (IGF) signaling is one of the best conserved and characterized mechanisms to extend longevity. Pregnancy associated plasma protein A (PAPP-A) is a secreted metalloprotease that increases IGF availability by cleaving IGF binding proteins. PAPP-A inhibition reduces local IGF signaling, limits the progression of multiple age-related diseases, and extends lifespan, but the mechanisms behind these pleiotropic effects remains unknown. Here, we developed and utilized a PAPP-A neutralizing antibody to discover that adulthood inhibition of this protease reduced collagen and extracellular matrix (ECM) gene expression in multiple tissues in mice. Using bone marrow to explore this effect, we identified mesenchymal stromal cells (MSCs) as the source of PAPP-A and primary responders to PAPP-A inhibition. Short-term treatment with anti-PAPP-A reduced IGF signaling in MSCs, altered MSC expression of collagen/ECM, and decreased MSC number. This affected MSC-dependent functions, decreasing myelopoiesis and osteogenesis. Our data demonstrate that PAPP-A inhibition reduces the activity and number of IGF-dependent mesenchymal progenitor cells and their differentiated progeny, and that this reduction leads to functional changes at the tissue level. MSC-like cells are present in virtually all tissues, and aberrant collagen and ECM production from mesenchymal cells drives aspects of aging and age-related diseases, thus this may be a mechanism by which PAPP-A deficiency enhances lifespan and healthspan.SummaryInhibition of PAPP-A, a regulator of IGF signaling, decreases multi-tissue collagen and extracellular matrix gene expression and modulates mesenchymal stromal cell activity in murine bone marrow.

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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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The extracellular matrix phenome across species

10.1101/2020.03.06.980169 ◽

2020 ◽

Author(s):

Cyril Statzer ◽

Collin Y. Ewald

Keyword(s):

Extracellular Matrix ◽

Sonic Hedgehog ◽

Genetic Variants ◽

Association Studies ◽

Interaction Networks ◽

List Type ◽

C Elegans ◽

Age Related ◽

Genome Wide ◽

Molecular Components

AbstractExtracellular matrices are essential for cellular and organismal function. Recent genome-wide and phenome-wide association studies started to reveal a broad spectrum of phenotypes associated with genetic variants. However, the phenome or spectrum of all phenotypes associated with genetic variants in extracellular matrix genes is unknown. Here, we analyzed over two million recorded genotype-to-phenotype relationships across hundreds of species to define their extracellular matrix phenomes. By using previously defined matrisomes of humans, mice, zebrafish, Drosophila, and C. elegans, we found that the extracellular matrix phenome comprises of 3-10% of the entire phenome. Collagens (COL1A1, COL2A1) and fibrillin (FBN1) are each associated with more than 150 distinct phenotypes in humans, whereas collagen COL4A1, Wnt- and sonic hedgehog (shh) signaling are predominantly associated in other species. We determined the phenotypic fingerprints of matrisome genes and found that MSTN, CTSD, LAMB2, HSPG2, and COL11A2 and their corresponding orthologues have the most phenotypes across species. Out of the 42’558 unique matrisome genotype-to-phenotype relationships across the five species with defined matrisomes, we have constructed interaction networks to identify the underlying molecular components connecting with orthologues phenotypes and with novel phenotypes. Thus, our networks provide a framework to predict unassessed phenotypes and their potential underlying molecular interactions. These frameworks inform on matrisome genotype-to-phenotype relationships and potentially provide a sophisticated choice of biological model system to study human phenotypes and diseases.Highlights7.6% of the human phenome originates from variations in matrisome genes11’671 phenotypes are linked to matrisome genes of humans, mice, zebrafish, Drosophila, and C. elegansExpected top ECM phenotypes are developmental, morphological and structural phenotypesNonobvious top ECM phenotypes include immune system, stress resilience, and age-related phenotypes

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Thromboxane and prostacyclin differentially regulate murine extracellular matrix gene expression

Kidney International ◽

10.1038/ki.1993.172 ◽

1993 ◽

Vol 43 (6) ◽

pp. 1219-1225 ◽

Cited By ~ 31

Author(s):

Leslie A. Bruggeman ◽

Jill A. Pellicoro ◽

Elizabeth A. Horigan ◽

Paul E. Klotman

Keyword(s):

Gene Expression ◽

Extracellular Matrix ◽

Matrix Gene

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Extracellular matrix gene expression signatures as cell type and cell state identifiers

Matrix Biology Plus ◽

10.1016/j.mbplus.2021.100069 ◽

2021 ◽

pp. 100069

Author(s):

Fabio Sacher ◽

Christian Feregrino ◽

Patrick Tschopp ◽

Collin Y. Ewald

Keyword(s):

Gene Expression ◽

Extracellular Matrix ◽

Cell Type ◽

Cell State ◽

Matrix Gene ◽

Gene Expression Signatures

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Multi-environment phenotyping of C. elegans for robust evaluation of physical performance

10.1101/2020.08.17.253583 ◽

2020 ◽

Author(s):

Jennifer E. Hewitt ◽

Ricardo Laranjeiro ◽

Masoud Norouzi ◽

Rebecca Ellwood ◽

Adam Antebi ◽

...

Keyword(s):

Muscular Dystrophy ◽

Physical Performance ◽

Current Treatment ◽

Therapeutic Interventions ◽

Model Organisms ◽

C Elegans ◽

Drug Candidates ◽

Treatment Standard ◽

Drug Interventions

ABSTRACTDetermining the physical performance of humans using several measures is essential to evaluating the severity of diseases, understanding the role of environmental factors, and developing therapeutic interventions. Development of analogous measures of physical performance in model organisms can help in identifying conserved signaling pathways and prioritizing drug candidates. In this study, we propose a multi-environment phenotyping (MEP) approach that generates a comprehensive set of measures indicative of physical performance in C. elegans. We challenge C. elegans in different mechanical environments of burrowing, swimming, and crawling, each of which places different physiological demands on the animals to generate locomotory forces. Implementation of the MEP approach is done using three established assays corresponding to each environment–a hydrogel-based burrowing assay, the CeleST swim assay, and the NemaFlex crawling strength assay. Using this approach, we study individuals and show that these three assays report on unique aspects of nematode physiology, as phenotypic measures obtained from different environments do not correlate with one another. Analysis of a subset of genes representative of oxidative stress, glucose metabolism, and fat metabolism show differential expression depending on the animal’s environment, suggesting that each environment evokes a response with distinct genetic requirements. To demonstrate the utility of the MEP platform, we evaluate the response of a muscular dystrophy model of C. elegans dys-1 to drug interventions of prednisone, melatonin and serotonin. We find that prednisone, which is the current treatment standard for human Duchenne muscular dystrophy, confers benefits in all three assays. Furthermore, while the tested compounds improve the physical performance of dys-1, these compounds are not able to fully restore the measures to wild-type levels, suggesting the need for discovery efforts to identify more efficacious compounds that could be aided using the MEP platform. In summary, the MEP platform’s ability to robustly define C. elegans locomotory phenotypes demonstrates the utility of the MEP approach toward identification of candidates for therapeutic intervention, especially in disease models in which the neuromuscular performance is impaired.

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