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Understanding the Mechanisms of Dietary Restriction to Extend Healthy Lifespan in Drosophila Melanogaster Understanding the mechanisms of dietary restriction to extend healthy lifespan in Drosophila melanogaster Sahar Emran Thesis submitted for PhD 2015 Primary supervisor: Matthew Piper Secondary supervisor: David Gems Institute of Healthy Ageing Department of Genetics, Evolution & Environment University College London Abstract Dietary restriction (DR), defined as a moderate reduction in food intake short of malnutrition, has been shown to extend healthy lifespan in a diverse range of organisms, from yeast to primates. In this work we aim to uncover the mechanism by which DR extends lifespan. The prevailing theory of somatic maintenance by resource reallocation proposes that the balance of nutrient allocation is weighted either towards reproduction, when environmental nutrients are abundant, or towards maintenance of the soma when food is limited, thereby aiding organismal survival during food shortages. This theory has found support in reports that dietary restricted Drosophila melanogaster (fruit fly) benefit from increased lifespan but have compromised reproduction, and that the inverse is true of fully fed flies. It has recently been found that addition of the ten essential amino acids (EAA) to a DR diet is sufficient to decrease lifespan and increase fecundity to the same degree as full feeding, implicating EAAs as the dietary mediators of the responses of lifespan and fecundity to DR. In this thesis I characterise the physiological and metabolic parameters that define DR flies, fully fed flies and EAA- supplemented DR flies, with the aim of identifying candidate factors that consistently correlate with lifespan for the three treatments in order to identify the causes of longer life in response to DR. We also use genetic tools to explore the role of nutrient signalling pathways in mediating the relationship between nutrition and ageing, with special focus on the amino acid sensitive target of rapamycin (TOR) pathway, the insulin/insulin-like growth factor signalling (IIS) pathway, and the general amino acid control (GAAC) pathway. These studies find a role for TOR signalling in mediating the effects of DR on lifespan and this effect appears to be different from those caused by altered IIS and GAAC pathways. These data also implicate accumulation of fat as consistently correlated with, and so possibly causal for, longer life. Finally, I investigated the potential roles that these nutrient sensing/signalling pathways might play in modifying feeding behaviour in response to changes in dietary nutrient quality. Here, the GAAC pathway proved to play an important and specific role in the way single amino acid deficient foods are detected to alter feeding behavior. These data are somewhat consistent with mammalian studies on nutrient-specific feeding alterations and establish the groundwork for detailed studies into the molecular processes involved. As a combined body of work, this thesis outlines important data on the mechanisms of DR to extend life as well as new information about the nutrients and molecular signals involved in shaping feeding choices. 2 Declaration I confirm that the work presented in this thesis is my own. Where information has been derived from other sources, this has been duly indicated within the thesis. _______________________________ Sahar Emran 3 Acknowledgements Foremost I thank my supervisor, Matt Piper, for being an excellent teacher and mentor. I express my deepest gratitude for the time and effort he has dedicated to my academic development, which has never been short of generous, and for his inexhaustible patience. It has been my privilege to have worked on such an enjoyable project with such a great scientist. I thank Matt Hoddinott and Helena Cochemé for showing me the fly pusher ropes. I thank my colleagues in the Piper lab, past and present - Mingyao Yang, Xiaoli He, Peter Rennert, Adam Dobson, Jelle Zandveld, Christina Lin and Caitlin Smith - for their insightful discussions, advice, and contributions to this work. I also thank my secondary supervisor, Professor David Gems, and my tertiary supervisor, Professor Kevin Fowler, for their discussions and direction. I extend my gratitude to the Biotechnology and Biological Sciences Research Council (BBSRC), who partially funded this PhD. I am grateful to my friends at the Institute of Healthy Ageing who have each played a unique and invaluable part in making the lab an inspiring and stimulating place to work, and who have made my time here so enjoyable and memorable. I especially thank Yila de la Guardia and Jorge Iván Castillo-Quan, with whom I have shared much of this journey, through good times and better times. Thanks also to Ann Gilliat, Nazif Alic, Ekin Bolukbasi, Melissa Cabecinha, Gio Vinti, Julie Black, Cassie Coburn, Kerri Kinghorn, Filipe Cabreiro, Thomas Moens, Danny Filer, David McBay, Fiona Kerr and all other past and current members of the IHA, who are too great in number to list. I am also grateful to my friends outside of the lab, who have, with good intentions, imposed upon me a work-life balance: Fereshta Shams, Fereshta Omar, and Kudsia Kaker. I am thankful to Marzia Azizi, who first got me interested in ageing research. Last but not least, I am indebted to my family: my brothers Omaid and Emel, for always keeping it real, and for the unspoken love and moral support that they will deny providing me. I am eternally grateful to my parents, Saleh Emran and Aria Emran, to whom this thesis is dedicated - I thank them for the paths that they have paved for me, and for always being encouraging and accommodating of my academic endeavors. This thesis is also dedicated to my brother Wahid, who has taught me much about patience and endurance - "for you, a thousand times over". 4 Contents Abstract ................................................................................................................................ 2 Declaration ........................................................................................................................... 3 Acknowledgements .............................................................................................................. 4 Contents ................................................................................................................................ 5 Figures and Tables .............................................................................................................. 8 Abbreviations ..................................................................................................................... 10 Chapter 1 - General introduction .................................................................................... 11 1.1. Ageing ....................................................................................................................... 11 1.1.1. Evolutionary theories of ageing ................................................................................................... 12 1.1.2. Theories of the downstream mechanisms of ageing .................................................................... 17 1.1.3 Ageing research ............................................................................................................................ 19 1.1.4. Drosophila melanogaster as a model for ageing ......................................................................... 20 1.2. Dietary restriction ..................................................................................................... 24 1.2.1. Caloric restriction Vs. dietary restriction ..................................................................................... 26 1.2.2. Role of amino acids in dietary restriction .................................................................................... 27 1.3. Nutrient sensing/signalling pathways ....................................................................... 30 1.3.1. The target of rapamycin (TOR) pathway ..................................................................................... 31 1.3.2. The insulin/IGF signalling (IIS) pathway .................................................................................... 40 1.3.3. The general amino acid control (GAAC) pathway ...................................................................... 44 1.4. Aims and Objectives ................................................................................................. 50 Chapter 2 - Materials and methods ................................................................................. 52 2.1. Drosophila melanogaster stocks .............................................................................. 52 2.1.1. Wildtype flies ............................................................................................................................... 52 2.1.2. Transgenic flies ............................................................................................................................ 52 2.2. Drosophila food media ............................................................................................. 55 2.2.1. Standard laboratory food .............................................................................................................. 55 2.2.2. Specialised SY food ..................................................................................................................... 55 2.2.3. Defined medium........................................................................................................................... 57 2.2.4. Specialised defined media ...........................................................................................................
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