Please cite this article in press as: Rizzo, L.B., et al., The theory of bipolar disorder as an illness of accelerated aging: Implications for clinical care and research. Neurosci. Biobehav. Rev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2014.02.004 ARTICLE IN PRESS G Model NBR 1894 1–13 Neuroscience and Biobehavioral Reviews xxx (2014) xxx–xxx Contents lists available at ScienceDirect Neuroscience and Biobehavioral Reviews jou rn al h om epage: www.elsevier.com/locate/neubiorev Review The theory of bipolar disorder as an illness of accelerated aging: Implications for clinical care and research Lucas Bortolotto Rizzo a,b , Leonardo Gazzi Costa a,b , Rodrigo B. Mansur a,b,c , Q1 Walter Swardfager d , Síntia Iole Belangero b,e , Rodrigo Grassi-Oliveira f , Roger S. McIntyre c,d , Moisés E. Bauer f , Elisa Brietzke a,b,∗ a Program for Recognition and Intervention in Individuals in At-Risk Mental States (PRISMA), Department of Psychiatry, Federal University of São Paulo, São Paulo, Brazil b Interdisciplinary Laboratory of Clinical Neuroscience (LINC), Department of Psychiatry, Federal University of São Paulo, São Paulo, Brazil c Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, Ontario, Canada d Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada e Department of Morphology and Genetics, Federal University of São Paulo, São Paulo, Brazil f Institute of Biomedical Research and Faculty of Biosciences, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil a r t i c l e i n f o Article history: Received 29 August 2013 Received in revised form 17 December 2013 Accepted 5 February 2014 Keywords: Bipolar disorder Aging Biomarkers Neuroprogression Telomeres Inflammation Immunosenescence BDNF Oxidative stress Amyloid Cognition Molecular imaging a b s t r a c t Bipolar Disorder (BD) has been conceptualized as both a cyclic and a progressive disorder. Mechanisms involved in neuroprogression in BD remain largely unknown although several non-mutually exclusive models have been proposed as explanatory frameworks. In the present paper, we propose that the pathophysiological Q2 changes observed in BD (e.g. brain structural alterations, cognitive deficits, oxidative stress imbalance, amyloid metabolism, immunological deregulation, immunosenescence, neurotrophic deficiencies and telomere shortening) converge on a model of accelerated aging (AA). Aging can be under- stood as a multidimensional process involving physical, neuropsychological, and social changes, which can be highly variable between individuals. Determinants of successful aging (e.g environmental and genetic factors), may also confer differential vulnerability to components of BD pathophysiology and contribute to the clinical presentation of BD. Herein we discuss how the understanding of aging and senes- cence can contribute to the search for new and promising molecular targets to explain and ameliorate neuroprogression in BD. We also present the strengths and limitations of this concept. © 2014 Published by Elsevier Ltd. Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2. Neurobiological similarities between neuroprogression in BD and aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.1. Changes at the structural level . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.2. Changes at the functional levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.3. Changes at the molecular level . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.3.1. Increased oxidative stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.3.2. Disturbances in amyloid metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.4. Changes at the cellular level . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.4.1. Immunosenescence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.4.2. Reduction in neurotrophins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.4.3. Short telomeres . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 ∗ Corresponding author at: R. Pedro de Toledo, 669, 3 ◦ andar Vila Clementino, CEP: 04039-032 São Paulo, Brazil. E-mail address: elisabrietzke@hotmail.com (E. Brietzke). http://dx.doi.org/10.1016/j.neubiorev.2014.02.004 0149-7634/© 2014 Published by Elsevier Ltd. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48