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Effect of a Caloric Restriction Based On UNIVERSIDAD AUTÓNOMA DE MADRID FACULTAD DE CIENCIAS DEPARTAMENTO DE BIOLOGÍA DOCTORAL THESIS Biology PhD “Effect of a caloric restriction based on the Mediterranean diet and intake of traditional Mediterranean foods on the expression of microRNAs regulating molecular processes associated with aging” INSTITUTO MADRILEÑO DE ESTUDIOS AVANZADOS EN ALIMENTACIÓN (IMDEA FOOD INSTITUTE) VÍCTOR MICÓ MORENO Madrid, 2018 UNIVERSIDAD AUTÓNOMA DE MADRID FACULTAD DE CIENCIAS DEPARTAMENTO DE BIOLOGÍA DOCTORAL THESIS Biology PhD “Effect of a caloric restriction based on the Mediterranean diet and intake of traditional Mediterranean foods on the expression of microRNAs regulating molecular processes associated with aging” INSTITUTO MADRILEÑO DE ESTUDIOS AVANZADOS EN ALIMENTACIÓN (IMDEA FOOD INSTITUTE) Memoria presentada por: Víctor Micó Moreno Para optar al grado de: DOCTOR EN BIOLOGÍA Doña Lidia Ángeles Daimiel Ruíz, Doctora en Biología Celular y Genética por la Universidad Autónoma de Madrid, investigadora del Instituto IMDEA Alimentación, informa favorablemente la solicitud de autorización de defensa de la tesis doctoral con el Título: “Effect of a caloric restriction based on the Mediterranean diet and intake of traditional Mediterranean foods on the expression of microRNAs regulating molecular processes associated with aging”, presentada por Don Víctor Micó Moreno para optar al grado de Doctor en Biología. Este trabajo ha sido realizado en el Instituto Madrileño de Estudios Avanzados en Alimentación (IMDEA Alimentación) bajo su dirección, y cumple satisfactoriamente las condiciones requeridas por el Departamento de Biología de la Universidad Autónoma de Madrid para optar al Título de Doctor. Ha actuado como tutor académico, y presenta su conformidad el Dr. Carlos Francisco Sentís Castaño, vicedecano de Personal Docente e Investigador y profesor titular del Departamento de Biología de la Facultad de Ciencias de la Universidad Autónoma de Madrid. Y para que así conste, firman el presente informe: Carlos Francisco Sentís Castaño, Lidia Ángeles Daimiel Ruiz Vicedecano de Personal Docente Investigadora Junior e Investigador Nutritional Genomics and Profesor Titular Epigenomics Group Departamento de Biología Precision Nutrition and Obesity Facultad de Ciencias Universidad IMDEA Alimentación Autónoma de Madrid. Esta tesis ha sido realizada gracias a la financiación obtenida a través del Instituto de Salud Carlos III (FIS/AES PI14/01374 and PI17/00508), XIV edición de las Becas de Investigación Manuel de Oya otorgadas por la Fundación Cerveza y Salud, Ayudas Merck Serono de Investigación otorgadas por la Fundación Salud 2000 además de un contrato en IMDEA Alimentación financiado por fondos FEDER europeos así como fondos de la Comunidad Autónoma de Madrid. La realización de la estancia internacional de investigación ha sido financiada por Short-Term Scientific Mission program de POSITIVe Cost Action y por Exchange Award de The European Foundation for Alcohol Research “ERAB”. “Nada en la vida debe temerse, solo debe ser entendida” Marie Curie A mis padres Paco y Amparo A mi hermana Sara A Laura Durante la realización de esta tesis doctoral ha habido muchas personas con las que he compartido parte o todo el camino hasta llegar a su final, con los que he tenido la suerte de compartir muchísimas experiencias y, a los que esta tesis, y lo que ello ha significado, pertenece también y me gustaría recordar. A la Dra. Lidia Daimiel, directora de esta tesis, y a la que puedo considerar mi mentora en el mundo de la ciencia. Desde el año 2012, momento en el que entré en IMDEA alimentación realizando prácticas extracurriculares de la universidad bajo su tutoría, comenzamos un camino de 6 años que ha resultado en esta tesis. Gracias por acompañarme en el mundo de la ciencia y el apoyo y confianza depositado en mí. Al Prof. José María Ordovás, director del departamento, el cuál ha sido un placer trabajar en su grupo, y aprender de él. A todo PREDITEAM, Laura B., Javi, Laura D. y Paloma, sin vuestra ayuda y apoyo no hubiera sido posible presentar esta tesis, que también pertenece a vosotros. A Ruth, gracias por todo tu apoyo porque, aunque nos conocemos sólo desde hace un año y medio, me llevo una amistad, muchos buenos momentos y el programa “amadrina un becario”. A todos los estudiantes a los que he tenido la suerte de enseñar, porque también he aprendido mucho de vosotros. A todo el equipo de medicina y enfermería y administración de los centros de atención primaria que han participado en nuestros estudios, así como a todos los voluntarios. A todas las personas que tuve la suerte de conocer durante mi estancia en el King´s College London, pero en especial a la Dra. Ana Rodríguez Mateos por acogerme en su grupo y a “Los científicos”: Geoffrey, Paul y Michele. Thanks for all good moments in London guys! A todos los imdea@s, especialmente Mónica, Su, Silvia, Lara, Cris, Josune, María, Jorge y a todos los predocs que hemos compartido alegrías y penas durante la tesis, por todas las horas compartidas, todos los buenos momentos, todos los misterios e historias ocurridas en IMDEA tratados de ser descubiertos y, en definitiva, haber sido una segunda familia. A mis amig@s de CYTA, Ana, Laura, Mario, Miguel, Isa y Cris, por los momentos compartidos y por los momentos que aún nos queda por compartir. A todos mis compañeros “inmigrantes” del máster, pero en especial a Patri y Elena, por todos los buenos momentos y por finalmente entender que es la p en estadística. A Raquel, de Nutrición, por cumplir aquello que decíamos cuando estudiábamos ¿te imaginas que terminamos doctorándonos? A mis padres, Paco y Amparo, ya que todo lo que ha sucedido ha sido gracias a ellos y nunca habéis dejado de darme vuestro apoyo incondicional y a mi hermana Sara, que me has marcado el camino que yo he continuado y que nunca has dejado de apoyarme y confiar en mí. Y por último, me gustaría agradecer y dedicar esta tesis a Laura ya que esta tesis no hubiera sido posible sin todo su apoyo, cariño y comprensión. Gracias por ser mi compañera tanto en este camino como en la vida y estar siempre a mi lado tanto en los buenos como en los malos momentos INDEX INDEX ABSTRACT / RESUMEN ................................................................................................................... 1 ABBREVIATIONS ............................................................................................................................. 5 INTRODUCTION ............................................................................................................................ 11 1. Aging situation of European and Spanish population ......................................................... 13 2. Interventions focusing on increasing longevity and promoting healthy aging ................... 15 2.1 Pharmacological interventions .......................................................................................... 15 2.2 Interventions on lifestyle .................................................................................................. 16 2.3. Nutritional interventions .................................................................................................. 16 2.3.1. Evidences from studies in animal models ................................................................. 17 2.3.2. Evidences from studies in human populations ......................................................... 18 3. The Mediterranean Diet: a great allied in healthy aging ........................................................ 23 3.1 MD: a healthy diet pattern ................................................................................................ 23 3.2. The role of olive oil in health ............................................................................................ 24 3.3. The role of beer in health ................................................................................................. 25 3. Nutrient sensor pathways ................................................................................................... 27 4.1. Description of the IGF-1/PI3K/AKT/FOXO/mTOR and AMPK/SIRT1/PGC1α pathways and their role in metabolic and cardiovascular diseases ............................................................... 28 4.2. Relationship of nutrient sensing pathways with aging .................................................... 29 5. MicroRNAs ........................................................................................................................... 32 5.1. Synthesis and function of microRNAs .............................................................................. 32 5.2. Relationship between microRNAs and metabolism and metabolic diseases. Modulation mediated by diet. .................................................................................................................... 34 5.3. Circulating microRNAs: biomarkers of health status and response to treatment. .......... 35 5.4. MicroRNAs associated with aging .................................................................................... 36 5.5. Modulation mediated by microRNAs of nutrient sensing pathways ............................... 37 5.5.1. Regulation mediated by microRNAs of the IGF1/PI3K/AKT/mTOR pathway ............ 37 5.5.2. Regulation mediated by microRNAs of the AMPK/SIRT1/PGC1α pathway .............. 39 I INDEX 5.6. Effect of CR on the levels of microRNAs........................................................................... 39 5.7. Exogenous microRNAs ....................................................................................................
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