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Sleep, Metabolism and Aging

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Sleep, Metabolism and Aging Unicentre CH-1015 Lausanne http://serval.unil.ch Year: 2014 Sleep, metabolism and aging LUCA, Gianina LUCA, Gianina 2014 Sleep, metabolism and aging Originally published at : Thesis, University of Lausanne Posted at the University of Lausanne Open Archive. http://serval.unil.ch Document URN : urn:nbn:ch:serval-BIB_78308E12B5165 Droits d’auteur L'Université de Lausanne attire expressément l'attention des utilisateurs sur le fait que tous les documents publiés dans l'Archive SERVAL sont protégés par le droit d'auteur, conformément à la loi fédérale sur le droit d'auteur et les droits voisins (LDA). A ce titre, il est indispensable d'obtenir le consentement préalable de l'auteur et/ou de l’éditeur avant toute utilisation d'une oeuvre ou d'une partie d'une oeuvre ne relevant pas d'une utilisation à des fins personnelles au sens de la LDA (art. 19, al. 1 lettre a). A défaut, tout contrevenant s'expose aux sanctions prévues par cette loi. Nous déclinons toute responsabilité en la matière. Copyright The University of Lausanne expressly draws the attention of users to the fact that all documents published in the SERVAL Archive are protected by copyright in accordance with federal law on copyright and similar rights (LDA). Accordingly it is indispensable to obtain prior consent from the author and/or publisher before any use of a work or part of a work for purposes other than personal use within the meaning of LDA (art. 19, para. 1 letter a). Failure to do so will expose offenders to the sanctions laid down by this law. We accept no liability in this respect. Centre Intégratif de Génomique Sleep, metabolism, and aging Thèse de doctorat ès sciences de la vie (PhD) présentée à la Faculté de biologie et de médecine de l’Université de Lausanne par Gianina Luca Docteur en médicine, diplômée de l’Université de Médicine et Pharmacie « Gr.T. Popa » Iasi, Roumanie Jury Prof. Joseph Ghika, Président Prof. Mehdi Tafti, Directeur de thèse Prof. Yves Dauvilliers, expert Prof. François Pralong, expert Dr. Liliane Michalik, expert Lausanne 2014 1 Table of contents 1. Acknowledgments………………………………………………………………………....2 2. Abstract ...………………………………………………………………………..……..... 4 3. Résumé …………………………………………………..………….…….....……………5 4. Résumé pour un large public ……………………………………………...….………....7 5. Introduction ………………………………………...…………..………….……………..9 5.1.Sleep architecture ...…………………………………………………..………….….. 13 5.2.Neurobiology of sleep and wakefulness and sleep regulation ..……….…………… 14 5.3.Main EEG sleep characteristics …………………………………………………….. 19 5.4.Sleep and aging ………………………………………….………………….......…... 20 5.5.Sleep pharmacology ………………………………………………………........….....24 5.6.Gamma-hydroxybutyrate ………………………………………....………..……….. 25 6. Research outline and main results ………………………………….……….……….. 30 7. Discussions and perspectives ………………………………………….…………...…. 33 8. References ………………………………………………………..….……………..…... 39 9. Age and gender-related sleep changes in the general normal population …………. 53 10. Central and peripheral effects of gamma-hydroxybutyrate ………………………... 82 11. Annex 1 ……………………………………………………………………….……..... 139 12. Annex 2 ……………………………………………………………………………...... 170 1 1. Acknowledgements There are a number of people without whom this thesis might not have been written, and to whom I am greatly indebted. To my supervisor, Professor Mehdi Tafti, who let me grow-up in a stimulant, comforting and rich environment. For your patience, for your continuous encouragement, for being remarkably available, for your generosity and support, for your confidence in letting me discover the magic world of real sleep research, for all of these and many more, thank you! I would like to warmly thank Professor Yves Dauvilliers, Professor Francois Pralong, Dr. Liliane Michalik and Professor Joseph Ghika, for having accepted to be part of my thesis committee. I shared this path with the greatest team: Tafti’s group. Thank you, guys! I was privileged to have Corinne, Annick and Julie (my “Swiss homing persons”, my French teachers, and my friends) and Christina by my side. Thank you, Angelique, Sonia, and Yann, for your invaluable help, your support and your open spirit. Also, many thanks to Cyril, Ali, Anne, and Sha for their originality, for the long discussions and for encouragements. To Paul Franken, many thanks for accepting me in your lab 5 years ago. It was an unforgettable and pleasant experience. Many thanks to the extraordinary CIRS team, especially Dr. Raphael Heinzer, Dr. Jose Haba-Rubio, Nadia Tobback, Daniela Andries, and Gianpaolo Lecciso for your help and kindness. Thank you to all participants in the HypnoLaus study for making that research possible and of course, to NINA team with whom I spent a great time, especially Alessandra Rossi. 2 To the first people who showed me the beauty of sleep medicine: Professor Traian Mihaescu, Dr. Sinziana Lovin, Dr. Verona Mihai, many thanks for trusting me, initiating me, and for being there for me for better and for worse. A warm thank you to Professor Viorel Scripcariu, Professor Lucian Miron, Professor Dragos Negru, Dr. Vasile Drug, Dr. Dorothea Wagner, Dr. Nermin Halkic and Dr. Michael Montemurro, who magically helped me to win a battle against the odds. For their unconditional love and support, for the precious advices, and their kindness, I wish I could say “thank you” to Alexandra and Gheorghe Luca and to Hrisi Ioanu, who left too soon. I miss you and I wish you were here! Many thanks to my family for constant support. Thank you, mom, for your love and care! Thank you, Jo and Dorin for long late night discussions, for your interminable list of questions, and for your fine criticism. Thanks to my adoptive families, Nicorici and Rudiko, for the great time, for care and support. Finally, thank you, Doru, my best friend, the most reliable shoulder, my greatest fan, my love, and my husband. I couldn’t have done it without you! 3 2. Abstract Aging is a multidimensional process of physical, psychological, and social changes. Understanding how we sleep and how this dynamic process evolves across life span will help to identify normal developmental aspects of sleep over time and to create strategies to increase awareness of sleep disturbances and their early management. In normal sleepers from HypnoLaus cohort, we evaluated the effects of age and gender on both subjective and objective sleep measurements. Our results indicate that normal aging is not accompanied by sleep complaints, and when they exist suggest the presence of underlying comorbidities. Polysomnographic data revealed that slow wave sleep was more affected with age in men, and age affected differently NREM and REM spectral power densities. Both sleep structure and spectral analysis profiles may constitute standards to delineate pathological changes in sleep, both for aging women and men. Another important aspect in the management of sleep and its disorders is a detailed characterization of sleep-inducing medications. Gamma-hydroxybutyrate (GHB) is an inhibitory neurotransmitter derivative of GABA, but its mode of action and the range of effects are not well understood. Several properties, as growth hormone stimulation in humans and the development of weight loss in treated patients suggest an unexplored metabolic effect. In different experiments we assessed the effects of acute, short term and chronic GHB administration on central (cerebral cortex) and peripheral (liver) biochemical processes involved in the metabolism of the drug, as well as the effects of the drug on metabolism in C57BL/6J, GABAB knock-out and obese (ob/ob) mice. We showed that GHB treatment affects weight gain in C57BL/6J and GABAB knock-out mice. Metabolomic analysis indicated large central and peripheral metabolic changes induced by GHB with important relevance to its therapeutic use. 4 3. Résumé Le vieillissement est un processus multidimensionnel accompagné par de multiples changements dans les domaines physique, psychologique et social. Comprendre comment nous dormons et comment ce processus dynamique évolue sur la durée de vie nous aidera à identifier les aspects normaux du développement du sommeil au fil du temps, et à créer des stratégies pour accroître la connaissance et compréhension des troubles du sommeil et leur prise en charge précoce. Chez les sujets normaux de la cohorte HypnoLaus nous avons évalué les effets de l'âge et du sexe sur les mesures subjectives et objectives du sommeil. Nos résultats indiquent que le vieillissement normal ne s'accompagne pas de troubles du sommeil, et quand ils existent ceux-ci suggèrent la présence de comorbidités sous-jacentes. Les données polysomnographiques ont révélé que le sommeil profond était plus affecté avec l'âge chez les hommes. De plus, nous avons montré comment l'âge modifie la composition spectrale du sommeil lent et paradoxal. La structure du sommeil et les profils d'analyse spectrale peuvent donc constituer des standards permettant de définir les changements pathologiques du sommeil chez les personnes âgées. Parmi les aspects importants de la gestion du sommeil et de ses troubles, la caractérisation détaillée des médicaments hypnotiques utilisés est essentielle. L’acide gamma-hydroxybutyrique (GHB) est un acide gras à courte chaîne dérivé du GABA, principal neurotransmetteur inhibiteur du cerveau, mais son mode d'action et tous ses effets sont toujours largement méconnus. Plusieurs propriétés, comme la stimulation de la sécrétion de l'hormone de croissance chez l'homme et le développement d’une perte de poids chez les patients traités suggèrent un effet métabolique
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