La chondroïtine pour vivre plus longtemps ?

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Youthful and age-related matreotypes predict drugs promoting longevity
Cyril Statzer Aging Cell, Vol. 20, No. 9, September 2021 04 August 2021

The identification and validation of drugs that promote health during aging (“geroprotectors”) are 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 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 Caenorhabditis 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.

Traitement à l'âge adulte (commencé au jour 2 de l'âge adulte) de chondroïtine ou d'acide hyaluronique sur la durée de vie.


Traitement à la glucosamine sur la durée de vie.

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Drug Screening Implicates Chondroitin Sulfate as a Potential Longevity Pill
Collin Y. Ewald Front. Aging, 08 September 2021 | https://doi.org/10.3389/fragi.2021.741843

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.

[Nutrimuscle-Conseils]

Le sulfate de chondroïtine est trouvé abondamment dans les tissus conjonctifs, tels que le cartilage qui amortit les extrémités des os dans les articulations, la peau, les vaisseaux sanguins, les ligaments et les tendons, mais aussi dans d'autres organes, tels que le cerveau...

Ainsi, le sulfate de chondroïtine est un candidat idéal pour se développer davantage en un composé géroprotecteur.

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D-Glucosamine supplementation extends life span of nematodes and of ageing mice
Sandra Weimer Nat Commun . 2014 Apr 8;5:3563.

D-Glucosamine (GlcN) is a freely available and commonly used dietary supplement potentially promoting cartilage health in humans, which also acts as an inhibitor of glycolysis. Here we show that GlcN, independent of the hexosamine pathway, extends Caenorhabditis elegans life span by impairing glucose metabolism that activates AMP-activated protein kinase (AMPK/AAK-2) and increases mitochondrial biogenesis. Consistent with the concept of mitohormesis, GlcN promotes increased formation of mitochondrial reactive oxygen species (ROS) culminating in increased expression of the nematodal amino acid-transporter 1 (aat-1) gene. Ameliorating mitochondrial ROS formation or impairment of aat-1-expression abolishes GlcN-mediated life span extension in an NRF2/SKN-1-dependent fashion. Unlike other calorie restriction mimetics, such as 2-deoxyglucose, GlcN extends life span of ageing C57BL/6 mice, which show an induction of mitochondrial biogenesis, lowered blood glucose levels, enhanced expression of several murine amino-acid transporters, as well as increased amino-acid catabolism. Taken together, we provide evidence that GlcN extends life span in evolutionary distinct species by mimicking a low-carbohydrate diet.

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Loss of Chondroitin Sulfate Modification Causes Inflammation and Neurodegeneration in skt Mice
Erica L Macke Genetics. 2020 Jan;214(1):121-134.

One major aspect of the aging process is the onset of chronic, low-grade inflammation that is highly associated with age-related diseases. The molecular mechanisms that regulate these processes have not been fully elucidated. We have identified a spontaneous mutant mouse line, small with kinky tail (skt), that exhibits accelerated aging and age-related disease phenotypes including increased inflammation in the brain and retina, enhanced age-dependent retinal abnormalities including photoreceptor cell degeneration, neurodegeneration in the hippocampus, and reduced lifespan.

By positional cloning, we identified a deletion in chondroitin sulfate synthase 1 (Chsy1) that is responsible for these phenotypes in skt mice. CHSY1 is a member of the chondroitin N-acetylgalactosaminyltransferase family that plays critical roles in the biosynthesis of chondroitin sulfate, a glycosaminoglycan (GAG) that is attached to the core protein to form the chondroitin sulfate proteoglycan (CSPG). Consistent with this function, the Chsy1 mutation dramatically decreases chondroitin sulfate GAGs in the retina and hippocampus. In addition, macrophage and neutrophil populations appear significantly altered in the bone marrow and spleen of skt mice, suggesting an important role for CHSY1 in the functioning of these immune cell types.

Thus, our study reveals a previously unidentified impact of CHSY1 in the retina and hippocampus. Specifically, chondroitin sulfate (CS) modification of proteins by CHSY1 appears critical for proper regulation of immune cells of the myeloid lineage and for maintaining the integrity of neuronal tissues, since a defect in this gene results in increased inflammation and abnormal phenotypes associated with age-related diseases.

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Ageing affects chondroitin sulfates and their synthetic enzymes in the intervertebral disc
Estelle C Collin, Signal Transduct Target Ther. 2017; 2: 17049.

The depletion of chondroitin sulfates (CSs) within the intervertebral disc (IVD) during degenerative disc disease (DDD) results in a decrease in tissue hydration, a loss of fluid movement, cell apoptosis, a loss of nerve growth inhibition and ultimately, the loss of disc function. To date, little is known with regards to the structure and content of chondroitin sulfates (CSs) during IVD ageing. The behavior of glycosaminoglycans (GAGs), specifically CSs, as well as xylosyltransferase I (XT-I) and glucuronyltransferase I (GT-I), two key enzymes involved in CS synthesis as a primer of glycosaminoglycan (GAG) chain elongation and GAG synthesis in the nucleus pulposus (NP), respectively, were evaluated in a bovine ageing IVD model. Here, we showed significant changes in the composition of GAGs during the disc ageing process (6-month-old, 2-year-old and 8-year-old IVDs representing the immature to mature skeleton). The CS quantity and composition of annulus fibrosus (AF) and NP were determined. The expression of both XT-I and GT-I was detected using immunohistochemistry. A significant decrease in GAGs was observed during the ageing process. CSs are affected at both the structural and quantitative levels with important changes in sulfation observed upon maturity, which correlated with a decrease in the expression of both XT-I and GT-I. A progressive switch of the sulfation profile was noted in both NP and AF tissues from 6 months to 8 years. These changes give an appreciation of the potential impact of CSs on the disc biology and the development of therapeutic approaches for disc regeneration and repair.

[Nutrimuscle-Diététique]

Traduction de l'étude

Le vieillissement affecte les sulfates de chondroïtine et leurs enzymes synthétiques dans le disque intervertébral
Estelle C Collin, Signal Transduct Target Ther. 2017 ; 2: 17049.

L'épuisement des sulfates de chondroïtine (CS) dans le disque intervertébral (IVD) au cours d'une discopathie dégénérative (DDD) entraîne une diminution de l'hydratation des tissus, une perte de mouvement des fluides, une apoptose cellulaire, une perte d'inhibition de la croissance nerveuse et, finalement, la perte de la fonction disque. À ce jour, on sait peu de choses sur la structure et la teneur en sulfates de chondroïtine (CS) au cours du vieillissement IVD. Le comportement des glycosaminoglycanes (GAG), en particulier des CS, ainsi que de la xylosyltransférase I (XT-I) et de la glucuronyltransférase I (GT-I), deux enzymes clés impliquées dans la synthèse des CS en tant qu'amorce de l'allongement de la chaîne des glycosaminoglycanes (GAG) et de la synthèse des GAG dans le noyau pulpeux (NP), respectivement, ont été évalués dans un modèle IVD de vieillissement bovin. Ici, nous avons montré des changements significatifs dans la composition des GAG au cours du processus de vieillissement du disque (DIV de 6 mois, 2 ans et 8 ans représentant le squelette immature à mature). La quantité de CS et la composition de l'anneau fibreux (AF) et de la NP ont été déterminées. L'expression de XT-I et GT-I a été détectée par immunohistochimie. Une diminution significative des GAG a été observée au cours du processus de vieillissement. Les CS sont affectées aux niveaux structurel et quantitatif avec des changements importants de sulfatation observés à maturité, qui sont corrélés à une diminution de l'expression de XT-I et GT-I. Un changement progressif du profil de sulfatation a été noté dans les tissus NP et AF de 6 mois à 8 ans. Ces changements donnent une appréciation de l'impact potentiel des CS sur la biologie du disque et le développement d'approches thérapeutiques pour la régénération et la réparation du disque.

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Brain ageing changes proteoglycan sulfation, rendering perineuronal nets more inhibitory
Simona Foscarin Aging (Albany NY). 2017 Jun; 9(6): 1607–1622.


Chondroitin sulfate (CS) proteoglycans in perineuronal nets (PNNs) from the central nervous system (CNS) are involved in the control of plasticity and memory. Removing PNNs reactivates plasticity and restores memory in models of Alzheimer’s disease and ageing. Their actions depend on the glycosaminoglycan (GAG) chains of CS proteoglycans, which are mainly sulfated in the 4 (C4S) or 6 (C6S) positions. While C4S is inhibitory, C6S is more permissive to axon growth, regeneration and plasticity. C6S decreases during critical period closure. We asked whether there is a late change in CS-GAG sulfation associated with memory loss in aged rats. Immunohistochemistry revealed a progressive increase in C4S and decrease in C6S from 3 to 18 months. GAGs extracted from brain PNNs showed a large reduction in C6S at 12 and 18 months, increasing the C4S/C6S ratio. There was no significant change in mRNA levels of the chondroitin sulfotransferases. PNN GAGs were more inhibitory to axon growth than those from the diffuse extracellular matrix. The 18-month PNN GAGs were more inhibitory than 3-month PNN GAGs.

We suggest that the change in PNN GAG sulfation in aged brains renders the PNNs more inhibitory, which lead to a decrease in plasticity and adversely affect memory.

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Chondroitin 6-sulphate is required for neuroplasticity and memory in ageing
Sujeong Yang Mol Psychiatry. 2021 Jul 16.

Perineuronal nets (PNNs) are chondroitin sulphate proteoglycan-containing structures on the neuronal surface that have been implicated in the control of neuroplasticity and memory. Age-related reduction of chondroitin 6-sulphates (C6S) leads to PNNs becoming more inhibitory. Here, we investigated whether manipulation of the chondroitin sulphate (CS) composition of the PNNs could restore neuroplasticity and alleviate memory deficits in aged mice.

We first confirmed that aged mice (20-months) showed memory and plasticity deficits. They were able to retain or regain their cognitive ability when CSs were digested or PNNs were attenuated. We then explored the role of C6S in memory and neuroplasticity. Transgenic deletion of chondroitin 6-sulfotransferase (chst3) led to a reduction of permissive C6S, simulating aged brains. These animals showed very early memory loss at 11 weeks old.

Importantly, restoring C6S levels in aged animals rescued the memory deficits and restored cortical long-term potentiation, suggesting a strategy to improve age-related memory impairment.

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Traduction de l'étude

Le 6-sulfate de chondroïtine est nécessaire à la neuroplasticité et à la mémoire du vieillissement
Psychiatrie Sujeong Yang Mol. 16 juillet 2021.

Les réseaux périneuronaux (PNN) sont des structures contenant des protéoglycanes de sulfate de chondroïtine sur la surface neuronale qui ont été impliquées dans le contrôle de la neuroplasticité et de la mémoire. La réduction liée à l'âge des 6-sulfates de chondroïtine (C6S) rend les PNN plus inhibiteurs. Ici, nous avons examiné si la manipulation de la composition en sulfate de chondroïtine (CS) des PNN pouvait restaurer la neuroplasticité et atténuer les déficits de mémoire chez les souris âgées.

Nous avons d'abord confirmé que les souris âgées (20 mois) présentaient des déficits de mémoire et de plasticité. Ils étaient capables de conserver ou de retrouver leurs capacités cognitives lorsque les CS étaient digérés ou que les PNN étaient atténués. Nous avons ensuite exploré le rôle du C6S dans la mémoire et la neuroplasticité. La suppression transgénique de la chondroïtine 6-sulfotransférase (chst3) a conduit à une réduction du C6S permissif, simulant des cerveaux âgés. Ces animaux ont montré une perte de mémoire très précoce à l'âge de 11 semaines.

Il est important de noter que la restauration des niveaux de C6S chez les animaux âgés a sauvé les déficits de mémoire et restauré la potentialisation corticale à long terme, suggérant une stratégie pour améliorer les troubles de la mémoire liés à l'âge.

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Risk of acute myocardial infarction among new users of chondroitin sulfate: A nested case-control study
Ramón Mazzucchelli PLoS One. 2021; 16(7): e0253932.

Objective
To test the hypothesis that the use of chondroitin sulfate (CS) or glucosamine reduces the risk of acute myocardial infarction (AMI).

Design
Case-control study nested in a primary cohort of patients aged 40 to 99 years, using the database BIFAP during the 2002–2015 study period. From this cohort, we identified incident cases of AMI and randomly selected five controls per case, matched by exact age, gender, and index date. Adjusted odds ratios (AOR) and 95% confidence interval (CI) were computed through a conditional logistic regression. Only new users of CS or glucosamine were considered.

Results
A total of 23,585 incident cases of AMI and 117,405 controls were included. Of them, 89 cases (0.38%) and 757 controls (0.64%) were current users of CS at index date, yielding an AOR of 0.57 (95%CI: 0.46–0.72). The reduced risk among current users was observed in both short-term (<365 days, AOR = 0.58; 95%CI: 0.45–0.75) and long-term users (>364 days AOR = 0.56; 95%CI:0.36–0.87), in both sexes (men, AOR = 0.52; 95%CI:0.38–0.70; women, AOR = 0.65; 95%CI:0.46–0.91), in individuals over or under 70 years of age (AOR = 0.54; 95%CI:0.38–0.77, and AOR = 0.61; 95%CI:0.45–0.82, respectively) and in individuals at intermediate (AOR = 0.65; 95%CI:0.48–0.91) and high cardiovascular risk (AOR = 0.48; 95%CI:0.27–0.83), but not in those at low risk (AOR = 1.11; 95%CI:0.48–2.56). In contrast, the current use of glucosamine was not associated with either increased or decreased risk of AMI (AOR = 0.86; 95%CI:0.66–1.08).

Conclusions
Our results support a cardioprotective effect of CS, while glucosamine seems to be neutral. The protection was remarkable among subgroups at high cardiovascular risk.

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Traduction de l'étude

Risque d'infarctus aigu du myocarde chez les nouveaux utilisateurs de sulfate de chondroïtine : une étude cas-témoin nichée
Ramon Mazzucchelli PLoS One. 2021 ; 16(7) : e0253932.

Objectif
Tester l'hypothèse selon laquelle l'utilisation de sulfate de chondroïtine (CS) ou de glucosamine réduit le risque d'infarctus aigu du myocarde (IAM).

Concevoir
Étude cas-témoins nichée dans une cohorte primaire de patients âgés de 40 à 99 ans, utilisant la base de données BIFAP durant la période d'étude 2002-2015. À partir de cette cohorte, nous avons identifié des cas incidents d'IAM et sélectionné au hasard cinq témoins par cas, appariés selon l'âge exact, le sexe et la date de l'index. Les rapports de cotes ajustés (AOR) et l'intervalle de confiance (IC) à 95 % ont été calculés par une régression logistique conditionnelle. Seuls les nouveaux utilisateurs de CS ou de glucosamine ont été pris en compte.

Résultats
Au total, 23 585 cas incidents d'IAM et 117 405 témoins ont été inclus. Parmi eux, 89 cas (0,38 %) et 757 témoins (0,64 %) étaient des utilisateurs actuels de césariennes à la date de l'indice, ce qui donne un AOR de 0,57 (IC à 95 % : 0,46 à 0,72). Le risque réduit chez les utilisateurs actuels a été observé à la fois chez les utilisateurs à court terme (<365 jours, AOR = 0,58 ; IC à 95 % : 0,45 à 0,75) et à long terme (>364 jours AOR = 0,56 ; IC à 95 % : 0,36 à 0,87 ), chez les deux sexes (hommes, AOR = 0,52 ; IC 95 % : 0,38-0,70 ; femmes, AOR = 0,65 ; IC 95 % : 0,46-0,91), chez les individus de plus ou de moins de 70 ans (AOR = 0,54 ; 95 %IC : 0,38-0,77 et AOR = 0,61 ; 95 % IC : 0,45-0,82, respectivement) et chez les individus présentant un risque cardiovasculaire intermédiaire (AOR = 0,65 ; 95 % IC : 0,48-0,91) et élevé (AOR = 0,48 ; 95 %IC : 0,27–0,83), mais pas chez les personnes à faible risque (AOR = 1,11 ; IC 95 % : 0,48–2,56). En revanche, l'utilisation actuelle de glucosamine n'était pas associée à une augmentation ou à une diminution du risque d'IAM (AOR = 0,86 ; IC à 95 % : 0,66 à 1,08).

conclusion
Nos résultats soutiennent un effet cardioprotecteur du CS, alors que la glucosamine semble être neutre. La protection était remarquable parmi les sous-groupes à haut risque cardiovasculaire.