Press coverage of the 2010 Aging Cell paper: a few examples 

Pour la Science

Comment l'ovocyte rajeunit

Lorsqu'on vieillit, nos cellules accumulent des défauts. Pourrait-on éliminer certains d'entre eux et ainsi rajeunir les cellules ? Un mécanisme observé sur l'ovocyte fournit des pistes de recherche.

Jean-Jacques Perrier

NIGMS-NIH

Le ver nématode Caenorhabditis elegans, un bon modèle pour étudier le vieilissement cellulaire.

Les protéines carbonylées sont marquées de façon à mesurer leur abondance dans les ovocytes en maturation (les plus récents étant à droite ; au-dessus, on voit l'ovaire et les précurseurs des ovocytes en méïose). L'ovocyte mature traverse ensuite la spermathèque (non visible à droite), où sont stockés les spermatozoïdes. Le signal jaune clair de carbonylation diminue brusquement (flèche rouge) au niveau de l’ovocyte le plus mature.

Plus les organismes vivants avancent en âge, plus l'ADN et les protéines de leurs cellules sont endommagés, en particulier sous l'action de petites molécules, les espèces réactives de l'oxygène, sous-produits de la respiration. C'est ce qui explique, en partie, que les maladies dégénératives et les cancers sont plus fréquents avec l'âge.

Les cellules sexuelles, les spermatozoïdes des mâles et les ovocytes des femelles, n'échappent pas à ce phénomène, à mesure que l'individu qui les produit vieillit. Or les embryons et les nouveau-nés issus de la fécondation — la fusion de ces cellules — ne sont pas vieux avant l'âge : leurs cellules ne comptent presque pas de composants endommagés, sauf exceptions pathologiques. C'est donc qu'il existe des processus de rajeunissement qui évitent la transmission à la nouvelle génération de composants « vieillis » provenant des cellules sexuelles. Jérôme Goudeau et Hugo Aguilaniu, de l'École normale supérieure de Lyon et du CNRS, ont mis en évidence l'un de ces processus chez un modèle animal, le ver nématode Caenorhabditis elegans.

Dans les cellules, les mutations et autres altérations de l'ADN sont naturellement réparées par divers mécanismes. De plus, la double division, ou méïose, que subissent les précurseurs des cellules sexuelles entraîne des recombinaisons génétiques grâce auxquelles les cellules sexuelles disposent d'un génome « neuf ». En revanche, les protéines du cytoplasme des cellules sont constamment altérées par le métabolisme, malgré des mécanismes de protection. Elles sont par exemple carbonylées, c'est-à-dire oxydées de façon irréversible par des composés à fonction C=O, qui se fixent sur certains acides aminés. Une machinerie cellulaire riche en enzymes, le protéasome, débarrasse normalement la cellule des protéines anormales en les dégradant en acides aminés, qui peuvent être recyclés dans la synthèse de nouvelles protéines. Mais le protéasome peut être débordé si les protéines dénaturées s'accumulent en trop grand nombre, voire bloqué lorsqu'elles forment des agrégats.

En 2006, le groupe de Thomas Nyström, de l'Université de Göteborg, avec lequel collaborait H. Aguilaniu, a montré que le développement embryonnaire de la souris s'accompagne de l'élimination des protéines endommagées dans les cellules dont dérive le nouveau-né, parallèlement à une augmentation de l'activité du protéasome. C'est un mécanisme similaire, mais plus précoce, que les deux chercheurs lyonnais mettent en évidence aujourd'hui sur l'ovocyte de C. elegans. Grâce à une technique détectant par des anticorps la réaction d'un composé chimique avec les groupes carbonyl, ils ont pu visualiser pour la première fois les protéines carbonylées dans l'ovocyte à différents stades de son développement, une fois la cellule fixée.

Ils ont d'abord confirmé que les protéines de cette cellule sont altérées par des composés carbonylés. Puis ils ont découvert que la quantité de protéines ainsi endommagées diminue brusquement dans l'ovocyte à la fin de sa maturation, au moment de la fécondation. Il semble que le début de la fécondation par un spermatozoïde envoie un signal à l'ovocyte qui déclenche le nettoyage de son cytoplasme, explique H. Aguilaniu. De plus, lorsque le fonctionnement du protéasome est inhibé de 10 à 20 pour cent par de petites molécules, ce ménage protéique ne se produit plus et la reproduction n'aboutit pas. On peut donc supposer que l'activation du protéasome est la cause du rajeunissement cellulaire de l'ovocyte. Cette activation serait elle-même sous le contrôle de gènes régulateurs qui s'exprimeraient sous l'effet de signaux intracellulaires, qu'il reste à identifier.

Science Knowledge

When older, our cells accumulate defects. Could we eliminate some of them and thus rejuvenate cells? A process observed on the oocyte provides avenues for research.

Most living organisms get older, the more DNA and proteins of their cells are damaged, particularly under the action of small molecules, reactive oxygen species, byproducts of respiration. This explains, in part, degenerative diseases and cancers are more common with age.

Sex cells, sperm cells of male and female oocytes, are not immune to this phenomenon, as the individual who is aging product. Gold embryos and newborns from fertilization – the fusion of these cells – are not old before: their cells do not rely almost damaged components, except as pathological. So there are rejuvenation process that avoid transmission to the new generation of components “aged” from the sex cells. Jerome Goudeau and Hugo Aguilaniu, École Normale Superieure de Lyon and CNRS, have highlighted one of these processes in an animal model, the nematode worm Caenorhabditis elegans.

In cells, mutations and other DNA damage are repaired naturally by various mechanisms. In addition, the double division, or meiosis, suffered the precursors of germ cells leads to genetic recombination by which sex cells have a genome “nine”. In contrast, proteins from the cytoplasm of the cells are constantly affected by metabolism, despite protective mechanisms. They are, for example carbonyl, that is to say oxidized irreversibly by compounds according to C = O, which bind to certain amino acids. Cellular machinery rich in enzymes, the proteasome, normally rids the cell of abnormal proteins by degrading them into amino acids, which can be recycled in the synthesis of new proteins. But the proteasome may be overloaded if the denatured proteins accumulate too many or blocked when they form aggregates.

In 2006, the group of Thomas Nystrom of Goteborg University, which collaborated with H. Aguilaniu showed that the embryonic development of mice is accompanied by the elimination of damaged proteins in cells with the new drift- born, along with an increase of proteasome activity. It is a similar mechanism, but earlier, the two researchers Lyon show today on the oocyte C. elegans. Using a technique by detecting antibodies reacting a chemical compound with the carbonyl groups, they were able to visualize for the first time carbonylated proteins in the oocyte at different stages of development, once the cell set.

They first confirmed that the proteins in the cell are altered by carbonyl compounds. Then they discovered that the amount of damaged proteins and decreases sharply in the late oocyte maturation, at the time of fertilization. It seems that the beginning of fertilization by a sperm sends a signal that triggers the oocyte cytoplasm cleaning, says H. Aguilaniu. Moreover, when the proteasome function is inhibited by 10 to 20 percent of small molecules, this household protein no longer occurs and reproduction is not successful. We can therefore assume that the activation of the proteasome causes cellular rejuvenation of the oocyte. This activation is itself under the control of regulatory genes that express themselves as a result of intracellular signals, it remains to be identified.

Science Daily

Understanding Aging by Studying Reproduction

ScienceDaily (Nov. 22, 2010) — Do examples of rejuvenation exist in nature? Yes, during reproduction! For the first time, a team from the Laboratoire de Biologie Moléculaire de la Cellule (CNRS/ENS Lyon/Université de Lyon 1) has managed to visualize, in the model organism C. elegans, the sudden "rejuvenation" of oocytes just before fertilization.

Published in the journal Aging Cell, this work opens new avenues for understanding ageing and the diseases that are associated with it.

Traditionally, studies on ageing compare elderly individuals with younger individuals or normal individuals with individuals with proven longevity. A study carried out by Hugo Aguilaniu's team at the Laboratoire de Biologie Moléculaire de la Cellule (CNRS/ENS Lyon/Université Lyon 1) tackled the issue under a conceptually new angle: do examples of rejuvenation exist in nature? They do indeed, quite simply during reproduction! The scientists sought to understand why newborn babies do not inherit the same risks of developing ageing diseases, such as cancers, as their parents.

What are the potential genetic mechanisms for this "rejuvenation"? The researchers based their work on a model organism for ageing studies, C. elegans. This nematode worm is small, transparent, hermaphrodite, and capable of self-fertilization. It reproduces very quickly and makes it possible to monitor every step of fertilization in a single organism.

Over time, carbonylation and oxidation damage proteins, the main constituent of our cells, and can therefore act as ageing markers. In their study, the scientists developed a technique to "visualize," in oocytes, the level of oxidation of proteins in cells. They firstly noted that the germline (of gametes) is oxidized, precluding the idea that the germline does not age. But, above all, they showed that at a precise stage of maturation of the oocytes the level of oxidation dropped suddenly. How? The researchers highlighted the role of the proteasome (which serves to degrade proteins) in this process. When it is inhibited, "rejuvenation" occurs with difficulty or not at all, thereby leading to sterility. During reproduction, the proteins in our cells are therefore "cleansed" and rejuvenated to form new, young individuals.

This study paves the way for a number of fascinating biological questions: what must individuals inherit from their parents and, on the other hand, what must they not inherit? How do we manage, each time we reproduce, to reduce the incidence of ageing diseases (cancer, neuro-degeneration, etc.)?

Cienca Diaria

Mecanismo de rejuvenescimento já está na natureza

Submitted by Ciência Diária on Wednesday, 17 November 2010Sem comentários

Tornar-se mais jovem pode parecer algo da ciência do futuro, mas uma equipe de cientistas descobriu que é possível encontrar mecanismos rejuvenescedores em organismos na natureza. Os cientistas do Laboratório de biologia molecular da célula (CNRS/ENS Lyon/Universidade Claude Bernard de Lyon) acabam de visualizar o rejuvenescimento de ovócitos do verme Caenorhabditis elegans antes da fertilização. O artigo foi publicado na revista Aging Cell recentemente. A descoberta abre caminhos para a compreensão do envelhecimento e doenças associadas a ele.

Tradicionalmente, os estudos sobre envelhecimento comparam os indivíduos idosos com os mais jovens, ou indivíduos normais com indivíduos com longevidade comprovada. Um estudo conduzido pela equipe de Hugo Aguilaniu abordou a questão sob um ângulo conceitualmente novo: existe na natureza exemplos de rejuvenescimento? Sim, no momento da reprodução! Os cientistas tentavam explicar qual a razão de crianças não herdarem o mesmo risco de desenvolver doenças do envelhecimento, como o câncer, de seus pais mais velhos.

Os pesquisadores investigaram um organismo que é modelo clássico para estudos sobre envelhecimento, o C. Elegans: este pequeno verme nematoide é transparente, hermafrodita, capaz de autofecundação e de reprodução rápida. É possível observar todas as etapas de fecundação neste organismo.

Constituinte principal das nossas células, as proteínas são danificadas ao longo do tempo por oxidação (a carbonilação é um tipo específico de oxidação irreversível) que pode ser usado como um marcador do envelhecimento. No estudo, os cientistas desenvolveram uma técnica para “ver”, em ovócitos, a taxa de oxidação de proteínas nas células. Pela primeira vez, eles constataram que a linha germinal (a de gametas) se oxida, eliminando a ideia de que esta linha não envelhece. Mais importante, eles mostraram que, numa fase de maturação dos ovócitos, a taxa de oxidação diminuiu de repente. Como? Os pesquisadores puseram em evidência o papel do proteassoma (que degrada as proteínas) no processo. Quando ele é inibido, é observado pouco, ou nenhum, “rejuvenescimento”, o que resulta na esterilidade dos indivíduos. Durante o processo de reprodução, existe, portanto, uma “limpeza” das proteínas de nossas células, a fim de rejuvenescê-las para formar bebês jovens.

O estudo abre as portas para muitas questões biológicas fascinantes: o que deve ser herdado dos pais? E, pelo contrário, o que não deve ser herdado? Como podemos reduzir a incidência de doenças do envelhecimento, como o câncer, a neurodegeneração e outras, cada vez que nos reproduzimos?