Durée de vie, génétique et axe somatotrope

Longtemps descriptive, la recherche sur le vieillissement a profondément changé depuis la découverte de gènes régulant la durée de vie. Isolés en criblant le génome de simples nématodes, la plupart de ces gènes appartiennent à une voie de signalisation hautement conservée au cours de l’évolution. Leurs orthologues chez les vertébrés sont les familles des gènes de l’insuline, de l’insulin-like growth factor (IGF) et de leurs voies de signalisation. Très étudiés et connus pour leurs rôles dans la prolifération, la différenciation, la survie cellulaire et le métabolisme intermédiaire, on découvre maintenant leurs multiples fonctions dans le contrôle de la longévité et dans les réponses au stress oxydant, une des causes majeures du vieillissement cellulaire. La signalisation IGF chez les mammifères dépend d’un ensemble de signaux endocriniens que constitue l’axe somatotrope. En effet, plusieurs composantes de cet axe hormonal régulent efficacement la longévité, ce qui a été élégamment démontré par une série de modèles de souris génétiquement modifiées. Il est de plus en plus évident que le contrôle du vieillissement met en jeu des régulations hormonales dont l’ampleur des implications commence à peine à être découverte.Research on ageing made a big leap forward when genes regulating lifespan were discovered about a decade ago. First isolated by screening the genome of the nematode Caenorhabditis elegans, most of these genes belong to an essential signalling pathway that is highly conserved during animal evolution. Orthologous genes in vertebrate species are the families of genes coding for insulin, insulin-like growth factors (IGF) and related proteins. Intensively studied and well-known for their pivotal roles in proliferation, differentiation, survival and metabolism of most cells, we now discover their multiples functions with respect to the control of longevity and their ability to modulate the cell’s responses to oxidative stress, a major cause of cellular and organismal ageing. The activity of IGF signalling in mammals depends on a complex interplay of endocrine signals that together constitute the somatotropic axis. Accordingly, several components of this hormone axis, like growth hormone or growth hormone releasing hormone receptors, regulate efficiently animal longevity, which has been elegantly demonstrated by studies performed in genetically modified mouse models. From this and other work, it becomes increasingly clear that the control of ageing is a question of hormonal regulations. We here present several of these models and discuss the respective contributions of insulin and IGF signalling to the regulation of lifespan. We review data on the Klotho gene that acts on lifespan via surprising and not yet fully understood molecular mechanisms, connecting this new, hormone-like substance to IGF and insulin signalling. We further report recent evidence showing that human lifespan might be controlled in similar ways. Finally, we shed some light on clinical GH treatment in humans, from an endocrinologist’s point of view

Resonant dynamics for the quintic non linear Schr\"odinger equation

We consider the quintic nonlinear Schr\"odinger equation (NLS) on the circle. We prove that there exist solutions corresponding to an initial datum built on four Fourier modes which form a resonant set, which have a non trivial dynamic that involves periodic energy exchanges between the modes initially excited. It is noticeable that this nonlinear phenomena does not depend on the choice of the resonant set. The dynamical result is obtained by calculating a resonant normal form up to order 10 of the Hamiltonian of the quintic NLS and then by isolating an effective term of order 6. Notice that this phenomena can not occur in the cubic NLS case for which the amplitudes of the Fourier modes are almost actions, i.e. they are almost constant.Comment: 32 pages, 4 figure

Role of miRNA in the Transmission of Metabolic Diseases Associated With Paternal Diet-Induced Obesity

The concept of Developmental Origins of Health and Diseases (DOHaD) recognizes that an unfavorable maternal environment alters the developmental trajectory of the fetus and can lead to long-term risk of developing chronic noncommunicable diseases. More recently, the concept of a paternal transmission [Paternal Origins of Health and Diseases (POHaD)] has emerged stressing the impact of paternal overweight or obesity on offspring’s health and development. While very few examples of paternal epigenetic inheritance of metabolic disorders have been evidenced in human, many experimental mouse models based on high-fat diet (HFD)-induced paternal obesity have been developed to breakdown molecular mechanisms involved in the process. Besides DNA methylation and chromatin structure, sperm short noncoding RNAs have been considered as the main epigenetic vector of inheritance of paternally environmentally induced changes. Among them, sperm miRNAs are one particular subspecies sensitive to environmental changes and obesity can modify the sperm miRNA profile. Once delivered into the zygote, these molecules might induce epigenetic modifications in the embryo, thereby leading to consequences for fetus development and offspring physical and metabolic health later on in life. Furthermore, some data also suggest that metabolic pathologies may be intergenerationally or transgenerationally transmitted

Vatalanib for metastatic gastrointestinal stromal tumour (GIST) resistant to imatinib: final results of a phase II study

BACKGROUND: Vatalanib (PTK787/ZK 222584) inhibits a few tyrosine kinases including KIT, platelet-derived growth factor receptors (PDGFRs) and vascular endothelial growth factor receptors (VEGFRs). We report efficacy and safety results of vatalanib in advanced gastrointestinal stromal tumour (GIST) resistant to imatinib or both imatinib and sunitinib. PATIENTS AND METHODS: Forty-five patients whose metastatic GIST had progressed on imatinib were enrolled. Nineteen (42.2%) patients had received also prior sunitinib. Vatalanib 1250 mg was administered orally daily. RESULTS: Eighteen patients (40.0%; 95% confidence interval (CI), 25.7-54.3%) had clinical benefit including 2 (4.4%) confirmed partial remissions (PR; duration, 9.6 and 39.4 months) and 16 (35.6%) stabilised diseases (SDs; median duration, 12.5 months; range, 6.0-35.6+ months). Twelve (46.2%) out of the 26 patients who had received prior imatinib only achieved either PR or SD compared with 6 (31.6%, all SDs) out of the 19 patients who had received prior imatinib and sunitinib (P = 0.324). The median time to progression was 5.8 months (95% CI, 2.9-9.5 months) in the subset without prior sunitinib and 3.2 (95% CI, 2.1-6.0) months among those with prior imatinib and sunitinib (P = 0.992). Vatalanib was generally well tolerated. CONCLUSION: Vatalanib is active despite its narrow kinome interaction spectrum in patients diagnosed with imatinib-resistant GIST or with imatinib and sunitinib-resistant GIST

Cortisol coregulation in fish

Cortisol coregulation, which is the up- or down-regulation of partners’ physiological stress responses, has been described for individuals with strong attachment bonds, e.g. parents and their children, and romantic relationship partners. Research into moderating effects on cortisol coregulation suggests stronger covariation among distressed partners. Whether cortisol coregulation is unique to humans or can also be found in other species that share universal features of the vertebrate stress response remains unexplored. Using a repeated measures approach and non-invasive waterborne hormone analysis, we test the hypothesis that dyads of three-spined stickleback fish (Gasterosteus aculeatus) coregulate their cortisol levels in shared environments. Dyadic cortisol levels were unrelated when cohabiting (home tank), but significantly covaried when sharing a more stressful (as indicated by higher cortisol levels) environment (open field). Time-lag analysis further revealed that open field cortisol levels were predicted by partner’s cortisol levels prior to the shared experience. To our knowledge, this study provides the first evidence for coregulatory processes on cortisol responses in a non-human animal that lacks strong bonds and social attachment relationships, suggesting a shared evolutionary origin of cortisol coregulation in vertebrates. From an adaptive perspective, cortisol coregulation may serve to reduce risk in challenging, potentially threatening situations

Role of Adipose Tissue microRNAs in the Onset of Metabolic Diseases and Implications in the Context of the DOHaD

The worldwide epidemic of obesity is associated with numerous comorbid conditions, including metabolic diseases such as insulin resistance and diabetes, in particular. The situation is likely to worsen, as the increase in obesity rates among children will probably lead to an earlier onset and more severe course for metabolic diseases. The origin of this earlier development of obesity may lie in both behavior (changes in nutrition, physical activity, etc.) and in children’s history, as it appears to be at least partly programmed by the fetal/neonatal environment. The concept of the developmental origin of health and diseases (DOHaD), involving both organogenesis and epigenetic mechanisms, encompasses such programming. Epigenetic mechanisms include the action of microRNAs, which seem to play an important role in adipocyte functions. Interestingly, microRNAs seem to play a particular role in propagating local insulin resistance to other key organs, thereby inducing global insulin resistance and type 2 diabetes. This propagation involves the active secretion of exosomes containing microRNAs by adipocytes and adipose tissue-resident macrophages, as well as long-distance communication targeting the muscles and liver, for example. Circulating microRNAs may also be useful as biomarkers for the identification of populations at risk of subsequently developing obesity and metabolic diseases

Vieillissement neuroendocrinien du complexe hypothalamo-hypophysaire chez le rat (criblage moléculaire, axe somatotrope et régulation de la prise alimentaire)

Nous avons évalué par macroarray l'influence du vieillissement du complexe hypothalamo-hypophysaire chez le rat Sprague Dawley, qui développe avec l'âge obésité et tumeur hypophysaire. Cette étude montre une baisse de la dépense énergétique (DE) avec l'âge et une augmentation de celle-ci en présence des tumeurs. La longévité non constante selon les souches suggère un vieillissement différent. Nous avons recherché l' existence de facteurs de prédiction de la longévité dans diverses souches, dont certaines dans 2 conditions nutritionnelles. Seul le rat Lou C se distingue : il ne devient pas obèse, présente peu de maladies associées à l'âge et une longévité accrue. Nous avons étudié cette souche ainsi que celle dont il dérive initialement : le rat Wistar.PARIS5-BU-Necker : Fermée (751152101) / SudocSudocFranceF

Decourtye L et al PLoS One 2017-Raw data-IGF-1 Induces GHRH Neuronal Axon Elongation during Early Postnatal Life in Mice.pdf

Raw data used for the publication by Decourtye et al PlosOne 201

Enriching Stress Research

Enriched environments are known to boost physical and mental health in rodents and humans. Now, Cao et al. (2010) report that environmental enrichment also suppresses tumor growth in mice by stimulating the hypothalamus to produce brain-derived neurotrophic factor that acts on the sympathetic nervous system to reduce leptin production in white fat tissue