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Senescent cells secrete bioactive molecules, including reactive oxygen species (ROS) and pro-inflammatory cytokines. Conversely, pro-inflammatory signalling stabilizes the senescent phenotype. Cell senescence and chronic low-level inflammation increase with age have been proposed as causal factors in ageing. In this thesis I demonstrate that senescent cells accumulate with age in mouse liver and are temporally and spatially associated with markers of oxidative stress and inflammation, including activation of hepatic stellate cells which is generally associated with fibrosis. Moreover, I show that hepatocyte senescence is driven by DNA damage at the level of telomeres as shown by an age-dependent exponential Increase in the number of TIF, occurring independently of telomere length. In order to test experimentally, a potential link between inflammation and cellular senescence, I analyzed markers of cell senescence and features of age-related functional decline in several tissues from mice lacking the transcription factor nfkb1-1. I found that compromised signalling through NF-KB led to a pro-inflammatory phenotype and stabilized cell senescence in vitro as well as in multiple tissues in vivo. Accordingly, regenerative capacity in the liver, absorptive area in the intestine, epidermal thickness of the skin and accumulated fat mass in various depots were all reduced and both healthspan and lifespan of nfkb 1-1- mice were shortened. This data shows for the first time that widespread cell senescence resulting from persistent pro- inflammatory signalling can seriously accelerate mammalian ageing.

Ageing is the progressive decline in physiological performance with age, which is almost universal amongst multicellular organisms. While understanding ageing is an important aim in biological research, our current understanding of how and why we age is incomplete. In this thesis, I examine how sexual selection affects the evolution and mechanistic basis of ageing. I then explore how diet affects lifespan and reproduction in either sex. Finally, I test the hypotheses that oxidative stress, which occurs when cellular levels of Reactive Oxygen Species exceed circulating antioxidant defences causes ageing (i.e. the free radical theory of ageing) and/or constrains life-history strategies. To ask these questions, I employ quantitative genetics in decorated crickets Gryllodes sigillatus to examine the genetic co(variance) of ageing, lifespan, reproductive effort, oxidative damage and antioxidant protection. In the Australian field cricket, Teleogryllus commodus, I apply the geometric framework of nutrition to examine how lifespan, reproductive effort, oxidative damage and antioxidant capacity respond to dietary manipulation. In G. sigillatus, I found that sexual selection caused divergent strategies of age-dependent reproductive effort across the sexes and that this, in turn, promoted different rates of ageing in males and females. I found a trade-off between early reproductive effort and ageing rate in both sexes, although this trade-off was more pronounced in females (Chapter 3). I then explored the mechanistic basis of these sex-specific life-history strategies and, in support of the free radical theory of ageing, I found that oxidative damage was greatest in the shortest lived sex (females) and was negatively genetically correlated with lifespan. Additionally, oxidative damage was a cost of female reproductive effort that accelerated ageing, showing that oxidative stress may mediate sex-specific life-history strategies in decorated crickets (Chapter 4). If sexual selection affects reproduction and lifespan it should promote sex-specific life-history responses to dietary manipulation. In Australian black field crickets Teleogryllus commodus, I found that males and females have distinct dietary optima for lifespan and reproductive effort and that diet mediated a trade-off between these traits. I found that mating affected responses to dietary manipulation and caused sexual dimorphism in dietary intake under choice (Chapter 5). However, oxidative stress did not explain these life-history responses to dietary manipulation across the sexes (Chapter 6): although oxidative damage was greatest in the shortest lived sex (i.e. females), diets that extended lifespan did not reduce oxidative damage. My thesis illustrates the importance of considering sexual selection when considering the evolution and mechanistic basis of ageing. It offers equivocal support for the free radical theory of ageing but shows that oxidative stress may help underpin sex-specific life-history strategies. However, my results highlight that unravelling the relationship between oxidative stress and life-history strategies across the sexes will be a very difficult task.

Le vieillissement est caractérisé par une diminution de la masse et la force musculaire entraînant une détérioration des performances physiques, appelée sarcopénie. L'atrophie musculaire peut être expliquée par un turnover protéique négatif, une détérioration des dynamiques mitochondriales, une diminution de la capacité de régénération du muscle ainsi que par l'apoptose des noyaux musculaires. La diminution de la sécrétion d'hormones anabolisantes et un stress oxydant (OS) chronique conduisant à des dommages oxydatifs excessifs, seraient impliqués dans ces modifications. L’Exercice physique et les thérapies de remplacement hormonales sont efficaces pour lutter contre la sarcopénie. Une restauration de l’homéostasie redox pourrait avoir un rôle central dans la lutte contre la sarcopénie et impliquerait une activation de la glucose-6-phosphate déshydrogénase.Les principaux objectifs de cette thèse étaient de déterminer in vivo, si un SO chronique dans le muscle âgé altère les voies de signalisation impliquées dans la sarcopénie, et de chercher si le retour à un fonctionnement normal de ces voies nécessite une restauration de l'homéostasie redox. Certains paramètres et leurs mécanismes pouvant intervenir sur le maintien ou la restauration du SO ont été recherchés.Dans une première, nous avons confirmé que la sarcopénie est associée au OS chez le rat. Puis nous avons constaté qu’un traitement à l'hormone de croissance chez le rat peut prévenir la sarcopénie via un effet antioxydant et myogénique, associé à une activation de la G6DPH.Une seconde étude a monté des souris transgéniques surexprimant G6PDH présentaient une amélioration de la composition corporelle et des performances physiques.Une dernière étude a montré que la surexpression de G6DPH diminuait les dommages oxydatifs de l'ADN au repos. De façon surprenante, la surexpression de la G6PDH n’a pas d’effet protecteur vis à vis du SO induit par les divers stimuli pro-oxydants. / Aging is characterized by a decrease in muscle mass and strength causing a deterioration of physical performance, called sarcopenia. Muscle atrophy can be explained by a negative protein turnover, impaired mitochondrial dynamics, a decreased muscle regeneration capacity and myonuclei apoptosis. A decreased production of anabolic hormones and a chronic oxidative stress (OS) which leads to excessive oxidative damage would be involved in these alterations. Physical exercise and hormone replacement therapies are effective to combat sarcopenia. The restoration of a redox homeostasis may play a central role in their beneficial effects and would involve an up-regulation of the glucose-6-phosphate dehydrogenase enzyme.The main objectives of this thesis were to determine in vivo to what extent a pro-oxidant redox status in aged muscle may modulate signaling pathways involved in sarcopenia, and to investigate whether return to their normal functioning requires a restoration of the redox homeostasis. The third objective was to identify actors and their possible cellular mechanisms in the maintenance and/or the restoration of the redox status.In a first study in old rats, we first confirmed that sarcopenia is associated with OS. In a second time, we found that a growth hormone replacement therapy in olds rats prevents sarcopenia by acting as a double-edged sword, antioxidant as well as myogenic, associated with an up-regulation of G6DPH.

Le vieillissement est un phénomène naturel, obligatoire et irréversible, souvent associé à un déclin des performances et des fonctions de l'organisme. Bien que les comportements nous renseignent sur l'état physiologique et neurologique de l'organisme, très peu d'études ont portées sur les relations entre l'âge et les comportements. La recherche de nouveaux modèles permettant d'appréhender cette relation pourrait donc être primordiale. Chez les araignées orbitèles, la toile est une structure géométrique complexe d'une apparente régularité. Sa construction résulte d'une succession de comportements organisés et répétés et chaque variation dans la structure de la toile peut être interpréter comme une variation comportementale de l'araignée lors de la construction. L'objectif de cette étude était de mettre en évidence des variations structurelles dans la géométrie de la toile de l'araignée Zygiella x-notata qui pourraient être corrélées au vieillissement de l'araignée, et de savoir comment le vieillissement agissait sur la mobilité de l'araignée lors de sa construction et lors de la capture des proies. Nos résultats montrent que le vieillissement a affecté les caractéristiques géométriques de la toile, le comportement de construction et le comportement de capture de l'araignée. Notre étude a permis de valider la pertinence de l'utilisation des araignées orbitèles et de leurs toiles géométriques comme modèles innovants pour l'étude des relations entre vieillissement et comportement / Ageing is an obligatory and natural progressive process often associated with a decline in organism functions and performances. Although behaviours inform us about the physiological and neurological state of an organism, relationship between behaviour and ageing remains largely misunderstood. Thus, the research of new animal models that could assess this relationship would be crucial. In orb weaving spiders, the web is a complex geometrical structure, which presents a visible regularity. Its construction results of a succession of organized and repeatable behaviours and each variation in web characteristics could be interpreted as a behavioural variation during web construction. The objective of this study was to highlight structural variations in web's structure of the spider Zygiella-x-notata, which were correlated with spider's age, and to know how ageing affected spider mobility during web construction and prey capture. Our results showed that ageing influenced the geometrical structure of the orb-web, and the spider web-building and prey capture behaviours. Our study allowed to validate the pertinence of the use of spiders and their orb web as innovative models for studies of relationships between ageing and behaviour

Les calpaïnes 1 et 2 sont des protéases à cystéine ubiquitaires et la calpastatine est leur inhibiteur naturel, également ubiquitaire. Les calpaïnes sont impliquées dans le développement de la réponse inflammatoire via l’activation par protéolyse partielle de plusieurs substrats (activation de NF-κB par le clivage de I-κBα, remodelage du cytosquelette des cellules inflammatoires, clivage de la protéine chaperonne HSP 90…).Il a été précédemment démontré que les calpaïnes favorisent le vieillissement neuronal. Nous avons pu montrer dans un modèle murin que l’inhibition in vivo des calpaïnes par la surexpression de calpastatine limite le vieillissement notamment rénal et vasculaire. L’inflammation liée au vieillissement ou « inflammaging » est considérablement réduite par l’inhibition spécifique des calpaïnes. Ceci est dû, au moins en partie, à l’effet des calpaïnes sur la production de cytokines pro-inflammatoires et sur la maturation de l’interleukine-1.Si les calpaïnes intracellulaires exercent un rôle pro-inflammatoire, les calpaïnes externalisées ont un effet anti-inflammatoire via le clivage de TLR2. Les calpaïnes peuvent en effet être excrétées hors des cellules via les transporteurs ABCA1. Dans le cadre d’un modèle murin de mélanome, nous avons pu montrer que l’inhibition des seules calpaïnes extracellulaires par la surexpression de calpastatine extracellulaire préserve TLR2 et limite ainsi la progression de la tumeur.Les calpaïnes intra- et extracellulaires sont des médiateurs majeurs de la réponse inflammatoire et modulent « l’inflammaging » ainsi que la réponse immune anti-tumorale. / Calpain 1 and 2 are cysteine proteases and calpastatin is their natural inhibitor. Calpains and calpastatin are ubiquitous. Calpains are involved in inflammatory response development via activation by partial proteolysis of several substrates (NF-kappaB activation by I-kappaBalpha cleavage, remodeling of inflammatory cells cytoskeleton, cleavage of chaperone protein HSP90 ... ). It has been previously shown that calpains promote neuronal aging. We have shown in a mouse model that inhibition of calpain by calpastatin overexpression limits renal and vascular aging. The inflammation associated with aging or "inflammaging" is considerably reduced by specific inhibition of calpain. This is due, at least in part, to calpain effect on production of pro-inflammatory cytokines and in maturation of interleukin-1 alpha. If intracellular calpains are pro-inflammatory, secreted calpains have an anti-inflammatory effect via cleavage of TLR2. Calpains can indeed be excreted out of the cells via the transporter ABCA1. In the context of a mouse model of melanoma, we have shown that inhibition of extracellular calpain by only extracellular calpastatin overexpression preserves TLR2 and thus limit the progression of the tumor.Calpains intra- and extracellular are major mediators of inflammatory response and modulate the "inflammaging" and the anti-tumor immune response.

L’objectif de ces travaux de thèse était d’avancer dans la connaissance des effets du vieillissement normal sur les capacités d’attention soutenue et les mécanismes de contrôle attentionnel qui les sous-tendent. A cette fin, nous avons combiné l’utilisation de mesures comportementales, subjectives, et électrophysiologiques (potentiels évoqués). Les résultats comportementaux mettent en évidence des effets différenciés de l’âge sur les capacités d’attention soutenue en fonction de l’approche utilisée : détérioration dans les tâches de détection, et préservation dans les tâches d’inhibition. Les données électrophysiologiques mettent en évidence plusieurs spécificités des seniors dans l’engagement des mécanismes de contrôle attentionnel en situation d’attention soutenue : une activation globalement plus importante de ces mécanismes, une activation maintenue ou augmentée de ces mécanismes au fil de la tâche, et une topographie plus frontale des régions qui les sous-tendent. / The purpose of this project was to gain more knowledge about the effects of normal aging on sustained attention ability and attentional control mechanisms underlying this ability. To that end, we combined the use of behavioral, subjective and electrophysiological (event-related potentials) measures. Behavioral results evidenced differential effects of age on sustained attention ability according to the approach used: deterioration in detection tasks, and preservation in inhibition tasks. Electrophysiological data evidenced several special features of seniors regarding the recruitment of attentional control mechanisms in a situation of sustained attention: overall greater activation of these mechanisms, stable or increased activation of these mechanisms over the course of the task, and a more frontal topography of the regions underlying these mechanisms.