Oxidative stress, neuroendocrine function and behavior in an animal model of extended longevity

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1 Oxidative stress, neuroendocrine function and behavior in an animal model of extended longevity Alessandra Berry

2 Alessandra Berry Oxidative stress, neuroendocrine function and behavior in an animal model of extended longevity Thesis, Leiden University April 21 st 2010 ISBN/EAN No parts of this thesis may be reprinted or reproduced or utilized in any form or by any electronic, mechanical or other means now known or hereafter invented, including photocopying and recording, or in any information storage or retrieval system without written permission of the copyright owner. 2010, Alessandra Berry Cover: Gustav Klimt: Three Ages of Woman (1905) Oil on canvas, 178 x 198 cm Galleria Nazionale d'arte Moderna, Rome, Italy (courtesy of Ministero per i Beni e le Attività Culturali) Printing: Centro Stampa De Vittoria S.r.l. Rome, Italy

3 Oxidative stress, neuroendocrine function and behavior in an animal model of extended longevity Proefschrift ter verkrijging van de graad van Doctor aan de Universiteit Leiden, op gezag van de Rector Magnificus prof. Mr. P.F. van der Heijden, volgens besluit van het College voor Promoties te verdedigen op woensdag 21 april 2010 klokke uur door Alessandra Berry geboren te Rome (Italië) in 1974

4 Promotiecommissie Promotor Co-promotor Prof. Dr. E.R. de Kloet Dr. F. Cirulli (ISS, Rome, Italië) Overige leden Prof. Dr. M. Danhof Dr. D.L. Champagne Prof. Dr. M.S. Oitzl Dr. J. Prickaerts (Universiteit Maastricht) Prof. Dr. P.E. Slagboom Prof. Dr. B. van de Water Prof. Dr. R.G.J. Westendorp The studies presented in this thesis were performed both at the Division of Medical Pharmacology, Leiden/Amsterdam Center for Drug Research (LACDR), Leiden University Medical Center, Leiden, The Netherlands and at the Section of Behavioral Neuroscience, Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità (ISS), Rome, Italy The printing of this thesis was financially supported by: LACDR, Jurriaanse Stichting and EU-LifeSpan

5 Nothing has such power to broaden the mind as the ability to investigate systematically and truly all that comes under your observation in life. Marcus Aurelius (April 26 th March 17 th Roman Emperor and Philosopher) To my family

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7 TABLE OF CONTENTS Preface CHAPTER 1 General Introduction 1 Aging and neurodegeneration 2 Oxidative stress 3 Stress and the HPA axis 4 Interaction between stress and oxidative stress 5 The animal model 6 Summary rationale and objectives 7 Experimental approach and outline of the thesis CHAPTER 2 Delayed aging has a cost: reduced fertility, redirection of maternal activities and earlier onset of puberty in p66 Shc-/- mice CHAPTER 3 Greater resistance to psychophysical stress in p66 Shc-/- adult mice, a model of delayed aging CHAPTER 4 Deletion of the life span determinant p66 Shc prevents increases in emotionality and pain sensitivity in mice CHAPTER 5 Deletion of the life span determinant p66 Shc improves performance in a spatial memory task, decreases levels of oxidative stress markers in the hippocampus and increases levels of the neurotrophin BDNF in adult mice CHAPTER 6 General discussion 1 Main findings 2 Perspectives 3 Conclusions Summary Samenvatting Alessandra Berry s Curriculum Vitae List of publications Acknowledgments

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9 PREFACE Aging can be defined as a multifactorial degenerative process resulting from the organism s loss of the ability to maintain homeostasis, ultimately leading to death. Aberrant hypothalamic-pituitary-adrenal (HPA) axis activity and elevated glucocorticoid (GC) levels have been associated to aging and age-related neurodegenerative pathologies. Evidence is mounting that stress and oxidative stress might act synergistically to induce or exacerbate the neuronal decay associated with aging. P66 Shc is an inducible redox enzyme which, when activated by stress, produces reactive oxygen species (H 2 O 2 ) to trigger apoptosis and its deletion has been shown to increase lifespan in mammals. In addition, a role for this gene in regulating the effect of insulin on the energetic metabolism in mice has been recently described. A growing body of evidence has shown a redox regulation of the function of the glucocorticoid receptors as nuclear transcription factors. The p66 Shc protein is widely expressed in the body, including GC target tissues such as pituitary and brain. The main question addressed in this thesis was whether the interactions linking oxidative stress and the neuroendocrine system represent a crucial determinant for the aging process in p66 Shc-/- mice. It was expected that the reduced levels of reactive oxygen species, characteristic of these long-lived subjects, would result in a more efficient regulation of the hypothalamic-pituitary-adrenal axis and hence in a delay of the aging process. With this purpose, the contribution of p66 Shc to behavioral and neuroendocrine regulations was assessed from early post-natal life to senescence. We show for the first time that in these mice increased longevity is associated to a slow down in physical and emotional aging, although such delay is not related to the expected interaction between oxidative stress and the neuroendocrine system. Mutant subjects are characterized by increased behavioral plasticity and lower emotionality at adulthood, in addition to a better physical performance and lower pain sensitivity at old age. These characteristics are associated with increased central levels of the neurotrophin Brain-derived neurotrophic factor, reduced markers of oxidative stress and greater resilience to stress-induced changes in the internal milieu. Notably, we show that the role of the p66 Shc gene on lifespan in complex organisms, such as mammals, is not merely related to its oxidative stress-related function but, more in general, to effects, emerging already at adulthood and involving specific signaling pathways in the brain, related primarily to energy homeostasis and emotional behavior, which indeed emerge as important determinants of healthspan during aging. Intriguingly, metabolic and emotional aspects in the p66 Shc mutants appear to be strictly related in a mutual interaction possibly affecting the development of the emotional phenotype in a nature-nurture fashion mediated by maternal behavior. In conclusion our results shed light on the role of oxidative stress and metabolic signals in the context of longevity and emotionality/mood disorders. In addition, they point to p66 Shc as a candidate genetic determinant in the trade-off between fertility and lifespan. 9

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