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

Deficiency in type 1 insulin-like growth factor receptor in mice protects against oxygen-induced lung injury

BACKGROUND: Cellular responses to aging and oxidative stress are regulated by type 1 insulin-like growth factor receptor (IGF-1R). Oxidant injury, which is implicated in the pathophysiology of a number of respiratory diseases, acutely upregulates IGF-1R expression in the lung. This led us to suspect that reduction of IGF-1R levels in lung tissue could prevent deleterious effects of oxygen exposure. METHODS: Since IGF-1R null mutant mice die at birth from respiratory failure, we generated compound heterozygous mice harboring a hypomorphic (Igf-1r(neo)) and a knockout (Igf-1r(-)) receptor allele. These IGF-1R(neo/- )mice, strongly deficient in IGF-1R, were subjected to hyperoxia and analyzed for survival time, ventilatory control, pulmonary histopathology, morphometry, lung edema and vascular permeability. RESULTS: Strikingly, after 72 h of exposure to 90% O(2), IGF-1R(neo/- )mice had a significantly better survival rate during recovery than IGF-1R(+/+ )mice (77% versus 53%, P < 0.05). The pulmonary injury was consistently, and significantly, milder in IGF-1R(neo/- )mice which developed conspicuously less edema and vascular extravasation than controls. Also, hyperoxia-induced abnormal pattern of breathing which precipitated respiratory failure was elicited less frequently in the IGF-1R(neo/- )mice. CONCLUSION: Together, these data demonstrate that a decrease in IGF-1R signaling in mice protects against oxidant-induced lung injury

Learning Word Embeddings: Unsupervised Methods for Fixed-size Representations of Variable-length Speech Segments

International audienceFixed-length embeddings of words are very useful for a variety of tasks in speech and language processing. Here we systematically explore two methods of computing fixed-length embeddings for variable-length sequences. We evaluate their susceptibility to phonetic and speaker-specific variability on English, a high resource language and Xitsonga, a low resource language, using two evaluation metrics: ABX word discrimination and ROC-AUC on same-different phoneme n-grams. We show that a simple downsampling method supplemented with length information can outperform the variable-length input feature representation on both evaluations. Recurrent autoencoders, trained without supervision, can yield even better results at the expense of increased computational complexity

Components of the Hematopoietic Compartments in Tumor Stroma and Tumor-Bearing Mice

Solid tumors are composed of cancerous cells and non-cancerous stroma. A better understanding of the tumor stroma could lead to new therapeutic applications. However, the exact compositions and functions of the tumor stroma are still largely unknown. Here, using a Lewis lung carcinoma implantation mouse model, we examined the hematopoietic compartments in tumor stroma and tumor-bearing mice. Different lineages of differentiated hematopoietic cells existed in tumor stroma with the percentage of myeloid cells increasing and the percentage of lymphoid and erythroid cells decreasing over time. Using bone marrow reconstitution analysis, we showed that the tumor stroma also contained functional hematopoietic stem cells. All hematopoietic cells in the tumor stroma originated from bone marrow. In the bone marrow and peripheral blood of tumor-bearing mice, myeloid populations increased and lymphoid and erythroid populations decreased and numbers of hematopoietic stem cells markedly increased with time. To investigate the function of hematopoietic cells in tumor stroma, we co-implanted various types of hematopoietic cells with cancer cells. We found that total hematopoietic cells in the tumor stroma promoted tumor development. Furthermore, the growth of the primary implanted Lewis lung carcinomas and their metastasis were significantly decreased in mice reconstituted with IGF type I receptor-deficient hematopoietic stem cells, indicating that IGF signaling in the hematopoietic tumor stroma supports tumor outgrowth. These results reveal that hematopoietic cells in the tumor stroma regulate tumor development and that tumor progression significantly alters the host hematopoietic compartment

Pathway-based factor analysis of gene expression data produces highly heritable phenotypes that associate with age

2Abstract. Statistical factor analysis methods have previously been used to remove noise components from high dimensional data prior to genetic asso-ciation mapping, and in a guided fashion to summarise biologically relevant sources of variation. Here we show how the derived factors summarising path-way expression can be used to analyse the relationships between expression, heritability and ageing. We used skin gene expression data from 647 twins from the MuTHER Consortium and applied factor analysis to concisely summarise patterns of gene expression, both to remove broad confounding influences and to produce concise pathway-level phenotypes. We derived 930 “pathway phe-notypes ” which summarised patterns of variation across 186 KEGG pathways (five phenotypes per pathway). We identified 69 significant associations of age with phenotype from 57 distinct KEGG pathways at a stringent Bon-ferroni threshold (P &lt; 5.38 × 10−5). These phenotypes are more heritable (h2 = 0.32) than gene expression levels. On average, expression levels of 16% of genes within these pathways are associated with age. Several significan

Phenotypic covariance of longevity, immunity and stress resistance in the Caenorhabditis nematodes

Background \ud Ageing, immunity and stresstolerance are inherent characteristics of all organisms. In animals, these traits are regulated, at least in part, by forkhead transcription factors in response to upstream signals from the Insulin/Insulin– like growth factor signalling (IIS) pathway. In the nematode Caenorhabditis elegans, these phenotypes are molecularly linked such that activation of the forkhead transcription factor DAF-16 both extends lifespan and simultaneously increases immunity and stress resistance. It is known that lifespan varies significantly among the Caenorhabditis species but, although DAF-16 signalling is highly conserved, it is unclear whether this phenotypic linkage occurs in other species. Here we investigate this phenotypic covariance by comparing longevity, stress resistance and immunity in four \ud Caenorhabditis species. \ud \ud Methodology/Principal Findings \ud We show using phenotypic analysis of DAF-16 influenced phenotypes that among four closely related Caenorhabditis nematodes, the gonochoristic species (Caenorhabditis remanei and Caenorhabditis brenneri) have diverged \ud significantly with a longer lifespan, improved stress resistance and higher immunity than the hermaphroditic species (C. elegans and Caenorhabditis briggsae). Interestingly, we also observe significant differences in expression levels between the daf-16 homologues in these species using Real-Time PCR, which positively correlate with the observed phenotypes. Finally, we provide additional evidence in support of a role for DAF-16 in regulating phenotypic coupling by using a combination of wildtype isolates, constitutively active daf-16 mutants and bioinformatic analysis. \ud \ud Conclusions \ud The gonochoristic species display a significantly longer lifespan (p < 0.0001)and more robust immune and stress response (p<0.0001, thermal stress; p<0.01, heavy metal stress; p<0.0001, pathogenic stress) than the hermaphroditic species. Our data suggests that divergence in DAF-16 mediated phenotypes may underlie many of the differences observed between these four species of Caenorhabditis nematodes. These findings are further supported by the correlative higher daf-16 expression levels among the gonochoristic species and significantly higher lifespan, immunity and stress tolerance in the constitutively active daf-16 hermaphroditic mutants

Phenotypic covariance of Longevity, Immunity and Stress Resistance in the Caenorhabditis Nematodes

Background: Ageing, immunity and stresstolerance are inherent characteristics of all organisms. In animals, these traits are regulated, at least in part, by forkhead transcription factors in response to upstream signals from the Insulin/Insulin–like growth factor signalling (IIS) pathway. In the nematode Caenorhabditis elegans, these phenotypes are molecularly linked such that activation of the forkhead transcription factor DAF-16 both extends lifespan and simultaneously increases immunity and stress resistance. It is known that lifespan varies significantly among the Caenorhabditis species but, although DAF-16 signalling is highly conserved, it is unclear whether this phenotypic linkage occurs in other species. Here we investigate this phenotypic covariance by comparing longevity, stress resistance and immunity in four Caenorhabditis species. \ud \ud Methodology/Principal Findings: We show using phenotypic analysis of DAF-16 influenced phenotypes that among four closely related Caenorhabditis nematodes, the gonochoristic species (Caenorhabditis remanei and Caenorhabditis brenneri) have diverged significantly with a longer lifespan, improved stress resistance and higher immunity than the hermaphroditic species (C. elegans and Caenorhabditis briggsae). Interestingly, we also observe significant differences in expression levels between the daf-16 homologues in these species using Real-Time PCR, which positively correlate with the observed phenotypes. Finally, we provide additional evidence in support of a role for DAF-16 in regulating phenotypic coupling by using a combination of wildtype isolates, constitutively active daf-16 mutants and bioinformatic analysis. \ud \ud Conclusions: The gonochoristic species display a significantly longer lifespan (p<0.0001) and more robust immune and stress response (p<0.0001, thermal stress; p<0.01, heavy metal stress; p<0.0001, pathogenic stress) than the hermaphroditic species. Our data suggests that divergence in DAF-16 mediated phenotypes may underlie many of the differences observed between these four species of Caenorhabditis nematodes. These findings are further supported by the correlative higher daf-16 expression levels among the gonochoristic species and significantly higher lifespan, immunity and stress tolerance in the constitutively active daf-16 hermaphroditic mutants