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Universidad Autónoma de Madrid Facultad de Medicina Departamento de Medicina Preventiva y Salud Pública, y Microbiología THE INFLUENCE OF NUTRITIONAL DETERMINANTS ON AGEING DOCTORAL THESIS Helena Sandoval Insausti Directors: Dra. Pilar Guallar Castillón Dr. Fernando Rodríguez Artalejo Madrid, 2019 DOCTORAL THESIS THE INFLUENCE OF NUTRITIONAL DETERMINANTS ON AGEING Influencia de determinantes nutricionales en el envejecimiento Helena Sandoval Insausti To my parents and brother Dr. Pilar Guallar Castillón and Dr. Fernando Rodríguez Artalejo, inform that the thesis entitled “The influence of nutritional determinants on ageing” is an original work carried out by Helena Sandoval Insausti under our guidance and supervision. This is an original work and has not been submitted to any university for the awarding of any diploma/degree. We verify that we have read the thesis, that it is well written and it demonstrates a thorough understanding of the scientific methodology. Pilar Guallar Castillón, MD, PhD Fernando Rodríguez Artalejo, MD, PhD Department of Preventive Medicine Department of Preventive Medicine and Public Health, and Microbiology and Public Health, and Microbiology School of Medicine School of Medicine Universidad Autónoma de Madrid. Universidad Autónoma de Madrid. This thesis has been partially supported by FIS grants 16/609 and PI 17/01709 (Instituto de Salud Carlos III, State Secretary of R+D+I and FEDER/FSE), Table of Contents ACKNOWLEDGEMENTS ..................................................................... viii LIST OF ABBREVIATIONS ..................................................................... x SUMMARY .................................................................................................. 3 RESUMEN ................................................................................................. 10 1. GENERAL INTRODUCTION ............................................................ 16 1.1. Ageing ............................................................................................................ 15 1.2. Frailty ............................................................................................................. 16 1.3. Falls ................................................................................................................ 17 1.4. Nutrition ......................................................................................................... 18 1.5. Protein intake ................................................................................................. 19 1.6. Ultra-processed food intake ........................................................................... 19 2. OBJECTIVES ........................................................................................ 23 3. Macronutrients Intake and Incident Frailty in Older Adults: A Prospective Cohort Study ......................................................................... 28 3.1 INTRODUCTION .......................................................................................... 30 3.2. METHODS .................................................................................................... 30 3.2.1. Study design and Population .......................................................................... 30 3.2.2. Study Variables .............................................................................................. 31 3.2.2.1. Diet ..................................................................................................................... 31 3.2.2.2. Frailty ................................................................................................................. 31 3.2.2.3. Other Variables .................................................................................................. 32 3.2.3. Statistical Analysis ......................................................................................... 33 3.3. RESULTS ...................................................................................................... 34 3.4. DISCUSSION ................................................................................................ 43 3.4.1. Protein intake ................................................................................................... 43 3.4.2. MUFA intake ................................................................................................... 45 4. Protein Intake and Risk of Falls: A Prospective Analysis in Older Adults .......................................................................................................... 48 4.1. INTRODUCTION ......................................................................................... 50 4.2. METHODS .................................................................................................... 50 4.2.1. Study design and Population .......................................................................... 50 4.2.2. Study Variables .............................................................................................. 51 4.2.2.1. Diet ..................................................................................................................... 51 4.2.2.2. Falls .................................................................................................................... 52 i 4.2.2.3. Other Variables .................................................................................................. 52 4.2.3. Statistical Analysis ......................................................................................... 53 4.3. RESULTS ...................................................................................................... 54 4.4. DISCUSSION ................................................................................................ 60 5. Ultra-processed Food Consumption and Incident Frailty: A Prospective Cohort Study of Older Adults ............................................. 65 5.1. INTRODUCTION ......................................................................................... 67 5.2. METHODS .................................................................................................... 68 5.2.1. Study Design and Population ......................................................................... 68 5.2.2. Study Variables .............................................................................................. 68 5.2.2.1. Diet ..................................................................................................................... 68 5.2.2.2. Frailty ................................................................................................................. 69 5.2.2.3. Other Variables .................................................................................................. 70 5.2.3. Statistical Analysis ......................................................................................... 70 5.3. RESULTS ...................................................................................................... 71 5.4. DISCUSSION ................................................................................................ 86 6. CONCLUSIONS.................................................................................... 89 7. REFERENCES ...................................................................................... 98 8. ACTIVITIES DURING THE TRAINING PERIOD........................113 ii List of tables Table 1. Odds ratios (95% confidence interval) of incident frailty according to quartiles of protein intake in the Seniors-ENRICA cohort study (N=1,822). Table 2. Odds ratios (95% confidence interval) of incident frailty according to quartiles of fatty acids intake in the Seniors-ENRICA cohort study (N=1,822). Table 3. Baseline characteristics of the study participants according to tertiles of total protein, animal protein, and vegetable protein intake in the Seniors-ENRICA cohort study (N=2,464). Table 4. Odds ratios (95% confidence interval) for the risk of falls according to tertiles of protein intake in the Seniors-ENRICA cohort study (N=2,464). Analyses were stratified by a weight loss of 4.5 kg or more in the preceding year. Table 5. Baseline characteristics of the cohort participants according to quartiles of ultra-processed food consumption as a percentage of total energy (% energy), in the Seniors-ENRICA cohort study (N=1,822). Table 6. Frailty risk according to ultra-processed food consumption quartiles in the Seniors-ENRICA cohort study expressed as a percentage of total energy (% energy) or as gram per day/weight of each subject (g/kg). N=1,822. Table 7. Odds ratios of frailty components according to ultra-processed food consumption quartiles in the Seniors-ENRICA cohort study expressed as a percentage of total energy (% energy) or as gram per day/weight of each subject (g/kg). N=1,822. Supplementary Table 1. Baseline characteristics of the participants included and not included in the analyses (N=2,614). Supplementary Table 2. Baseline characteristics of the study participants according to frailty status (N=1,822). Supplementary Table 3. Baseline nutritional intake of the study participants according to frailty status (N=1,822). iv Supplementary Table 4. Baseline characteristics of the study participants according to quartiles of macronutrient intake (N=1,822). Supplementary Table 5. Odds ratios (95% confidence interval) of the frailty components according to quartiles of intake of total protein, animal protein, and monounsaturated fatty acids in the Seniors-ENRICA cohort study