The theory of bipolar disorder as an illness of accelerated aging: Implications for clinical care and research

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ARTICLE IN PRESSG ModelBR 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.elsev ier .com/ locate /neubiorev

eview

he theory of bipolar disorder as an illness of accelerated aging:mplications for clinical care and research

ucas Bortolotto Rizzoa,b, Leonardo Gazzi Costaa,b, Rodrigo B. Mansura,b,c,alter Swardfagerd, Síntia Iole Belangerob,e, Rodrigo Grassi-Oliveira f,

oger S. McIntyrec,d, Moisés E. Bauer f, Elisa Brietzkea,b,∗

Program for Recognition and Intervention in Individuals in At-Risk Mental States (PRISMA), Department of Psychiatry, Federal University of São Paulo,ão Paulo, BrazilInterdisciplinary Laboratory of Clinical Neuroscience (LINC), Department of Psychiatry, Federal University of São Paulo, São Paulo, BrazilMood Disorders Psychopharmacology Unit, University Health Network, Toronto, Ontario, CanadaSunnybrook Research Institute, University of Toronto, Toronto, Ontario, CanadaDepartment of Morphology and Genetics, Federal University of São Paulo, São Paulo, BrazilInstitute of Biomedical Research and Faculty of Biosciences, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil

r t i c l e i n f o

rticle history:eceived 29 August 2013eceived in revised form7 December 2013ccepted 5 February 2014

eywords:ipolar disordergingiomarkerseuroprogressionelomeres

a b s t r a c t

Bipolar Disorder (BD) has been conceptualized as both a cyclic and a progressive disorder. Mechanismsinvolved in neuroprogression in BD remain largely unknown although several non-mutually exclusivemodels have been proposed as explanatory frameworks. In the present paper, we propose that thepathophysiological changes observed in BD (e.g. brain structural alterations, cognitive deficits, oxidativestress imbalance, amyloid metabolism, immunological deregulation, immunosenescence, neurotrophicdeficiencies 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, whichcan be highly variable between individuals. Determinants of successful aging (e.g environmental andgenetic factors), may also confer differential vulnerability to components of BD pathophysiology andcontribute 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

nflammationmmunosenescenceDNFxidative stressmyloid

neuroprogression in BD. We also present the strengths and limitations of this concept.© 2014 Published by Elsevier Ltd.

ognitionolecular imaging

ontents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002. Neurobiological similarities between neuroprogression in BD and aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

2.1. Changes at the structural level . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002.2. Changes at the functional levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002.3. Changes at the molecular level . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

2.3.1. Increased oxidative stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002.3.2. Disturbances in amyloid metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

2.4. Changes at the cellular level . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

Please cite this article in press as: Rizzo, L.B., et al., The theory of bipclinical care and research. Neurosci. Biobehav. Rev. (2014), http://dx.d

2.4.1. Immunosenescence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2.4.2. Reduction in neurotrophins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2.4.3. Short telomeres . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

∗ Corresponding author at: R. Pedro de Toledo, 669, 3◦ andar Vila Clementino, CEP: 040E-mail address: [email protected] (E. Brietzke).

ttp://dx.doi.org/10.1016/j.neubiorev.2014.02.004149-7634/© 2014 Published by Elsevier Ltd.

olar disorder as an illness of accelerated aging: Implications foroi.org/10.1016/j.neubiorev.2014.02.004

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3. Implications for research directed to clinical care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.1. Pharmacological strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

3.1.1. Current pharmacology modulating aging related mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.1.2. Sirtuins as possible new target . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

3.2. Non-pharmacological strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.2.1. Physical activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Acknowledgements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

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Normal aging is associated with alterations in brain structures.

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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. Introduction

Bipolar Disorder (BD) is a prevalent and often severe mood dis-rder where individuals experience disruptive episodes of maniar hypomania and depression (Anderson et al., 2012). Causes of BDemain largely unknown but probably involve a set of genetic andnvironmental factors, which interact during neurodevelopmento determine vulnerability to the disease (Brietzke et al., 2012a).enetic studies have implicated many chromosomal regions andandidate genes, but results have been inconsistent and oftenot replicable (Sullivan et al., 2012). Genome-wide Associantiontudies (GWAS) studies indicate that genetic susceptibility is deter-ined by a high number of genes, each with a small effect size

Sullivan et al., 2012).Although BD has been understood classically as a cyclic disease,

n the last 10 years evidence has accumulated supporting progres-ive features of BD (Berk et al., 2010; Fries et al., 2012; Mansur et al.,013), reconceptualizing BD as both a cyclic and progressive disor-er. The starting point for this hypothesis was the clinical evidencehat individuals in early and late stages of BD present substantialifferences in the severity of clinical presentation and response toreatment (Berk et al., 2011). There are robust data suggesting that

greater number of episodes, especially those of manic polarity,re associated with a decrease in the length of the euthymic inter-al between episodes, worsening of neurocognitive performance,ncreasing risk of suicide, and poorer response to both pharmaco-ogical and psychosocial treatments (Berk et al., 2010; Magalhaest al., 2012). Nonetheless, evidence has been mixed and progres-ive models of mental illness are not universally accepted (Zipurskyt al., 2012). At present, operationalization of the concept of neuro-rogression in clinical practice manifests mainly in the “staging” ofevere mental disorders, including BD (for a detailed review, pleaseee Kapczinski et al., 2009).

Mechanisms involved in neuroprogression remain largelynknown and only few explanatory models exist that could justify

neuroprogressive disease course. Among these, one of the mostccepted is the concept of Allostatic Load (AL). AL implicates chronictress in overactivating homeostatic mechanisms that are collec-ively beyond the capability of the organism, leading to progressionf clinical and neurobiological parameters (Brietzke et al., 2011;oldstein et al., 2009b; Grande et al., 2012; Kapczinski et al., 2008).owever, it has been difficult to quantify the impact of stress biol-gy on neuroprogression, in part due to mechanisms of resistancend resilience that can modulate the impact of stress (Brietzke et al.,012b).

Another nascent theoretical framework is the concept of BDs a disorder of accelerated aging (AA) (Simon et al., 2006;odhi et al., 2012). Aging in humans refers to a persistentecline in the age-specific fitness components of an organ-

sm due to internal physiological degeneration (Rose, 1991).ging can also be understood as a multidimensional process

Please cite this article in press as: Rizzo, L.B., et al., The theory of bipclinical care and research. Neurosci. Biobehav. Rev. (2014), http://dx.d

f physical, neuropsychological, and social changes. With respecto neuropsychological changes, the effect of aging is non-uniformcross domains. For instance, psychomotor processing speed and

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verbal memory performance decline with age, while knowledgeand wisdom can continue to expand. The rates of change in thesedomains differ between individuals and they can be modified bymany intervening genetic and environmental factors. A comple-mentary concept is the idea of senescence. The phenomenon ofcellular senescence was first described by Leonard Hayflick in 1961,referring to the limited capacity of isolated cells to proliferate inculture (the Hayflick Limit) (Hayflick and Moorhead, 1961), but theconcept can also be applied to whole organisms. For example, aftera period of near perfect renewal (in humans, between 20 and 35years of age), organismal senescence is characterized by the declin-ing ability to respond to stress, increasing homeostatic imbalanceand risk of disease.

Preliminary data suggest that individuals with BD present earlysenescent features consistent with AA. One of the most clinicallyconspicuous corollaries is the high prevalence and earlier age ononset of age related medical conditions e.g. cardiovascular con-ditions, hypertension, metabolic imbalances, autoimmunity andcancer (Crump et al., 2013; Czepielewski et al., 2013; Fagioliniet al., 2008; Goldstein et al., 2009a; McIntyre et al., 2005, 2006;Osby et al., 2001; Padmos et al., 2004; Rege and Hodgkinson, 2013;Soreca et al., 2008). In addition, the association between mooddisorders and dementia has been well recognized. Most studiesinclude individuals with Major Depressive Disorder (MDD), but arecent meta-analysis suggested that the association between BDand dementia might be stronger than that of MDD (da Silva et al.,2013). Although the degree of neurobiological overlap betweenthe two conditions remains a matter of debate, there is evidencethat inflammation, neurotrophic and amyloid cascades are alteredin both conditions (Aprahamian et al., 2013; Modabbernia et al.,2013).

Here we discuss how aging and senescence may contributeto the search for new and promising molecular targets to bet-ter understand neuroprogressive features of BD. Although somefindings are preliminary, we postulate they can be integrated ina new theoretical framework to better explain some elements ofBD pathophysiology.

2. Neurobiological similarities between neuroprogressionin BD and aging

Although there are few studies exploring aging in BD, there is asurprisingly high overlap between neurobiological mechanisms inthe two conditions, including progressive changes at the molecularand cellular levels, and in the structure and function of the centralnervous system (CNS).

2.1. Changes at the structural level

olar disorder as an illness of accelerated aging: Implications foroi.org/10.1016/j.neubiorev.2014.02.004

Post mortem and structural neuroimaging studies indicate thatthe human brain shrinks with age, with selective and differentialchanges that are not uniform or random. CNS volume atrophy is

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ndicated by reduced brain weight and volume, ventriculomegalynd sulcal expansion. Microscopic studies documented myelin pal-or, loss of neuronal bodies in the neocortex, the hippocampus andhe cerebellum, loss of myelinated fibers across the subcorticalerebrum, shrinkage and dysmorphology of neurons, accumula-ion of lipofuscin, rarefication of cerebral vasculature, reductionn synaptic density, deafferentation and loss of dendritic spinesRaz and Rodrigue, 2006). The main findings of magnetic reso-ance imaging studies include brain atrophy (total brain volume:.4–0.5% brain tissue loss per year); hippocampal volume loss (1.6%er year in normal individuals); white matter lesions as puncti-orm or early confluent lesions in periventricular or subcorticalistribution and cerebral microbleeds (prevalence more than 20%

n persons older than 60 years) (Allen et al., 2005; DeCarli et al.,005; Enzinger et al., 2005; Fotenos et al., 2005; Ikram et al., 2008;ernigan et al., 2001; van der Lijn et al., 2008; Vernooij and Smits,012).

BD is also associated with alterations in brain structures evi-enced by previous imaging studies that reported findings ofnlargement of the third and lateral ventricles; a reduction inhe gray matter volumes of the orbital and medial prefrontal cor-ex, ventral striatum and mesotemporal cortex and an increase inhe size of the amygdala (Hallahan et al., 2011; Konarski et al.,008; Lisy et al., 2011; Martinez-Aran et al., 2002). These neu-oanatomical changes tend to be more pronounced in patientsith repeated episodes (Lisy et al., 2011; Strakowski et al., 2002).

urthermore, one of the most consistently reported abnormalitiesn BD is an increased number and/or severity of white mat-er hyperintensities (WMH) (Mahon et al., 2010; Mahon et al.,009). The main findings of neuropathogical studies suggesteficits in neuroplasticity, particularly in cell resilience and con-ectivity (Connor et al., 2009; Harrison, 2002; Martinez-Arant al., 2002; Rajkowska, 2002) as well as data showing fewerligodendrocytes in prefrontal white matter (Vostrikov et al.,007).

.2. Changes at the functional levels

The tertiary association cortices, the neostriatum, and the cere-ellum are profoundly affected by aging throughout the adult

ifespan. Regional volumetric decline has been linked with domain-pecific declines in cognitive performance. For example, poorererformance on executive function tasks has been associated withmaller volume of the prefrontal cortex and increased white matteryperintensity burden. Skill acquisition performance is enhanced

n those individuals who show larger volumes of the striatum, pre-rontal cortex and cerebellum. Spatial memory performance haseen linked to hippocampal volume and the concentration of N-cetyl aspartate therein. In addition, entorhinal cortex shrinkageas been found to predict memory decline, even in healthy indi-iduals (Raz and Rodrigue, 2006).

BD is associated with cognitive impairment during acute phasesf illness and euthymia, with greater abnormalities reported asunction of more frequent episodes (Martinez-Aran et al., 2005;

artinez-Aran et al., 2004; Robinson et al., 2006). The most severempairments are seen in verbal working memory, response inhi-ition, sustained attention, psychomotor speed, abstraction andet-shifting (Martinez-Aran et al., 2007). These deficits in execu-ive function and verbal memory have been associated with poorerunctional outcomes (Torrent et al., 2006; Ustun, 1999) and burdenf illness associated with BD (Rosa et al., 2008). It is similar of indi-iduals with mild cognitive impairment and early dementia who

Please cite this article in press as: Rizzo, L.B., et al., The theory of bipclinical care and research. Neurosci. Biobehav. Rev. (2014), http://dx.d

requently report impairments in functioning such as poor perfor-ance in household management activities and in more advanced

unctions (Albert et al., 1999). Furthermore, impairments psychoso-ial functioning can take a progressive course (Rosa et al., 2012;

PRESSvioral Reviews xxx (2014) xxx–xxx 3

Rosa et al., 2011) and can be present during euthymia (Swannet al., 1999). Some authors have proposed that individuals with BDpresent an acceleration in age-related cognitive decline, when com-pared with healthy controls (Gualtieri and Johnson, 2008), althoughthere are some contrary data (Samame et al., 2013). Individualswith MDD, especially those who present the disorder in late life,carry a well-documented risk of dementia (Aprahamian et al., 2013;Osorio et al., 2013). The increased risk of dementia associated withmood disorders in epidemiological studies may be due to commonneuropathological changes shared by these disorders. The investi-gation of aging and senescence processes might lead to an improvedunderstanding of these associations (Gualtieri and Johnson, 2008).

2.3. Changes at the molecular level

2.3.1. Increased oxidative stressIncreased generation of reactive oxygen species (ROS) or dys-

regulation of anti-oxidant mechanisms can lead to the damage ofcellular components such as DNA, proteins and lipids (Andreazzaet al., 2009). Possible sources of ROS include changes in energygeneration and ATP production, for instance free radicals can begenerated during mitochondrial electron transport (Steckert et al.,2010). Other cell process can also generate ROS, including exces-sive dopaminergic transmission (due reductive potential of thisneurotransmitter and its metabolites) and increases in levels of glu-tamate leading to increases in levels of intracellular calcium andcytotoxicity (Berk et al., 2011). Under physiological conditions, theharmful potential of ROS is kept under control by enzymatic andnon-enzymatic antioxidant defense systems (Steckert et al., 2010).

As oxidative stress has been considered a major source of molec-ular and cellular damage, and aging can be understood as a lifelongprocess of cell damage, these two phenomena are presumablylinked. Key pathophysiological elements of several diseases relatedto aging cause end-organ damage through oxidative mechanisms,including chronic obstructive pulmonary disease (Ito et al., 2012),cancer (Ito et al., 2012), type II diabetes (Stadler, 2012), cardio-vascular disease (Penna et al., 2013), Parkinson’s disease (Torraoet al., 2012), and Alzheimer’s disease (Torrao et al., 2012). Thesedata initially lead to “the free radical theory of aging” supportedextensively by numerous in vivo and in vitro studies (Harman,2009). Cumulative oxidative stress causes DNA damage, reducesmechanisms of DNA repair, stimulates inflammatory activation andmodulates redox-sensitive transcriptional factors, such as activatorprotein (AP)-1 and nuclear factor-kappa B (NF-�B), which alter thetranscription of numerous genes, both adaptive and maladaptive,consequently disrupting homeostasis.

Increased oxidative stress and its cellular and molecular con-sequences have been found extensively in BD. In animal modelsof mania, increases in oxidative mediators such as thiobarbituricacid reactive substances (TBARS) are well documented (Ghedimet al., 2012). Studies that focused on individuals in manic episodesobserved increases in nitric oxide (NO) and TBARS, as well asdecreases in antioxidant enzymes, including superoxide dismutase(SOD) and catalase (CAT) (Gergerlioglu et al., 2007; Machado-Vieiraet al., 2007; Savas et al., 2002). Acute treatment with lithiumappears to have an antioxidant effect, as it was shown to affectTBARS, SOD and CAT levels (Machado-Vieira et al., 2007). The onlystudy that evaluated BD individuals in depressive episodes reportedhigher levels of NO and lower levels of SOD, which were alsoresponsive to pharmacological treatment (Selek et al., 2008).

olar disorder as an illness of accelerated aging: Implications foroi.org/10.1016/j.neubiorev.2014.02.004

While imbalances in oxidative stress can be detected in earlystages of disease, they tend to be more pronounced with increasingduration of illness or number of episodes, suggesting that oxidativestress might be a mechanism of neuroprogression and a source of

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lasma biomarkers to monitor the course of the disease (Andreazzat al., 2009; Berk et al., 2011; Magalhaes et al., 2012).

.3.2. Disturbances in amyloid metabolismAmyloid � (A�) peptides of 40 or 42 amino acids are formed after

equential cleavage of the amyloid precursor protein (APP), a transembrane glycoprotein of undetermined function, by successive

ction of the � and � secretases (Zhang et al., 2011). Alzheimer’sisease (AD) is characterized, from a neuropathological standpoint,y the extracellular deposition of the A� and by the intraneu-onal generation of neurofibrillary tangles, neuropil threads, andbnormal material in dystrophic nerve cell processes of neuriticlaques. These changes are also found in a large number of non-emented elderly people post-mortem. One difference betweenemented AD patients and nondemented elderly with AD-relatedathology is reflected by the distribution pattern of neurofibrillaryangles and A� deposits. The AD patients who manifest clinicalymptoms of dementia present a pattern of widespread lesionsccurring in many areas of the brain (all areas affected in nonde-ented patients plus in the brain stem and cerebellum) whereas

ondemented elderly people showed neurofibrillary tangles and� deposits restricted to distinct predilection sites (neocortex, allo-ortex, basal ganglia, and diencephalic nuclei) (Thal et al., 2004).

Alterations of A� peptides concentration in plasma from ADatients (i.e. reduced A� 42 and an increased A� 40/A� 42 ratio)re common findings in recent studies, and this alteration waslso found in patients suffering from MDD (Kita et al., 2009; Qiut al., 2007; Sun et al., 2007). The risk for dementia and for cogni-ive decline seems to be greater in patients with mood disordershan in the general population (Geerlings et al., 2008; Gualtieri andohnson, 2008). In BD, the number of affective episodes (Geerlingst al., 2008; Kessing and Andersen, 2004) and the presence of psy-hotic symptoms (Kessing and Andersen, 2004; Robinson et al.,006; Torres et al., 2007) have been implicated as additional riskactor. Another study on bipolar depressed patients, found a sig-ificant negative correlation between A� 42 plasma levels andhe duration of the illness, whereas a positive correlation wasetected between the A� 40/A� 42 ratio and the number of affectivepisodes (Piccinni et al., 2012).

Direct cytotoxic effects of A�, negative effects on monoamin-rgic transmission, and functional antagonism between brain-erived neurotrophic factor (BDNF) and A�, suggest the potential

nvolvement of A� in the pathophysiology of BD and cellular aging.tudies suggest that A� may exhibit functional interference withDNF actions, because BDNF stimulates glutamatergic transmis-ion and long-term potentiation (LTP) (Korte et al., 1995; Levinet al., 1998; Lue et al., 1999) whereas A� inhibits these phenomenaSnyder et al., 2005). Furthermore, A� can block the phosphory-ation of the transcription factor cAMP response element-bindingCREB) (Tong et al., 2001) and its nuclear translocation, inhibitinghe synthesis of BDNF (Arancio and Chao, 2007; Arvanitis et al.,007). The hypothesized increase in glutamatergic transmissionuring mood episodes (Kugaya and Sanacora, 2005; Machado-ieira et al., 2009; Yildiz-Yesiloglu and Ankerst, 2006) may play aole in the A�-mediated neurotoxicity, explaining the relationshipetween cognitive decline and the severity of the clinical coursef mood disorders, and the greater risk of developing dementiaeported in mood disorders (Geerlings et al., 2008; Gualtieri andohnson, 2008; Kessing and Andersen, 2004; Robinson et al., 2006;orres et al., 2007). It has been suggested that some presenta-ions may represent a prodromal manifestation of AD, or a subtypef amyloid-associate mood disorder characterized by cognitive

Please cite this article in press as: Rizzo, L.B., et al., The theory of bipclinical care and research. Neurosci. Biobehav. Rev. (2014), http://dx.d

mpairment and risk of dementia (Sun et al., 2007). More generally,ndividuals who present with considerable Alzheimer’s pathologyut who do not develop clinical dementia may be less suscep-ible to dementia due to greater “cognitive reserve” (i.e. greater

PRESSvioral Reviews xxx (2014) xxx–xxx

resilience to neuropathological processes by virtue of greater neu-ral substrate, higher premorbid IQ, extensive education, exercise,other lifestyle factors, etc.), which may be eroded by BD pathologyresulting in greater susceptibility to dementia in the presence ofthe same neuropathological burden.

2.4. Changes at the cellular level

2.4.1. ImmunosenescenceImmunosenescence refers to the decline of immunological func-

tion that occurs with aging. During aging, sustained low-gradeinflammatory activity gradually evolves and this is sometimesreferred to as “inflammaging” (Franceschi et al., 2007). In this con-text, healthy aging and longevity are likely result not only froma lower propensity to mount inflammatory responses but alsomaintenance of efficient anti-inflammatory networks (Franceschiet al., 2007). During aging, regulatory processes may fail to coun-teract the inflammatory responses consequent to exposure todamaging agents or to the lifelong acquired antigenic burden.Intriguing data from a large multi-ethnic cohort study suggeststhat cumulative pathogen exposure, particularly viral pathogenssuch as cytomegalovirus (CMV) and other herpes virus, can lead toincreased risks of vascular aging, and cognitive decline in later-life(Elkind et al.; Katan et al.; Swardfager and Black). Further investi-gation is needed, but it is possible that these infections, overwhelmthe diminishing capacity for immunoregulation/immunotoleracethat occurs with age, resulting in increased tissue damage. In ani-mal models, the inflammatory response to experimental infectionresolves more slowly in aged mice than in adult mice, which isassociated with prolonged depressive-like behavior in aged mice(Kelley et al.). According to this perspective, one key to successfulphysical, psychological and cognitive aging is decreased inflamma-tory activity without compromising an effective acute response tonew pathogens (Franceschi et al., 2007).

The paradigm of inflammaging has been largely accepted toexplain why age is an important risk factor for diseases such astype-2 diabetes, cardiovascular diseases and some types of can-cer (Macaulay et al., 2013). In addition, inflammaging has beenpostulated as an explanation for some neurobiological characteris-tics of Alzheimer’s disease. Patients with Alzheimer’s disease showincreased inflammatory activity compared to controls (Swardfageret al., 2010b) as do patients in the clinical mild cognitive impair-ment prodromal phase of the illness (Fuchs et al., 2013). There isevidence that IFN-� and other pro-inflammatory cytokines inter-act with processing and production of A� peptide, suggesting thatthe increased inflammatory activity that accompanies aging couldprecipitate, accelerate or exacerbate AD pathology (Giunta, 2008).Some treatments that counteract inflammaging have been pro-posed to prevent or treat AD, including celecoxib, naproxen, trifusaland indomethacin although limitations in trial design or uncer-tainty in these results limit their readiness for clinical application(de Jong et al., 2008; Gomez-Isla et al., 2008).

There is a consistent body of evidence suggesting that BD isassociated with a persistent and low intensity pro-inflammatorystates, which are more intense during mood episodes, especiallymanic episodes, and less intense in depressive episodes (Brietzkeet al., 2009b; Modabbernia et al., 2013). Even euthymia has beenassociated with detectable peripheral pro-inflammatory activity(Brietzke et al., 2009a). In the context of aging, blood cytokineconcentrations have been correlated with immune-stimulatedcatabolism of tryptophan and tyrosine, necessary precursors in thesynthesis of serotonin and dopamine, and this has been associ-

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ated with affective and neurovegetative symptoms, respectively(Capuron et al., 2011). This mechanism may apply to BD patientsearlier in life. For instance, the enzymes and final products of thekynurenine pathway, which catabolizes tryptophan, are increased

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n the cingulate cortex in BD (Miller et al., 2006, 2008). This has beenssociated with cognitive symptoms in mood disorders patientsnd proposed as a modifiable target for therapy (Wonodi andchwarcz, 2010).

BD patients exhibit other immunological alterations commonn elderly people; for instance higher proportions of circulatingD8+CD28− cells (do Prado et al., 2013; Wieck and Grassi-Oliveira,013), and lower proportions of regulatory T cells (do Pradot al., 2013; Wieck and Grassi-Oliveira, 2013) and increasedytomegalovirus (CMV) infection (Rizzo et al., 2013). CD8+CD28−

ells have lost the expression of the CD28 protein, which is neces-ary for their complete stimulation and clonal expansion. They havehort telomeres, impaired cytotoxic function, and they are resistanto apoptosis (Derhovanessian et al., 2009; Weng et al., 2009). Theroportion of CD8+CD28− cells increases with aging and a high fre-uency of CD28− cells in the elderly correlates with a less effectiveesponse to influenza virus vaccination (Goronzy et al., 2001) andith a higher risk of mortality (Olsson et al., 2000; Wikby et al.,

002). The main cause for the expansion of these senescent cellss related to infectious burden, particularly CMV infection. Afternfection with CMV, the body is not able to promote virus clearance,eading to chronic albeit asymptomatic infection. The long course ofhe infection promotes chronic immunological stimulation of spe-ific cells for CMV epitopes, and consequently restriction of themmunological repertoire (Almanzar et al., 2005; Ouyang et al.,003). Intriguingly, this effect is less pronounced other chronic

nfections (Pawelec and Derhovanessian, 2011). The motive is untilow not completely understood, but it is possible that CMV has aloser relation with the immunological system compared to othernfections, since dendritic and endothelial cells function as viraleservoirs (Benedict et al., 2008; Bentz et al., 2006; Tabata et al.,008).

.4.2. Reduction in neurotrophinsImpaired capacity for neuroplasticity has been proposed as a

ore-underlying feature of mood disorders, which may be relatedo both affective and cognitive symptoms as they affect the integrityf nodal brain structures and connectivity between them. Neu-oplasticity can be impaired by pro-inflammatory cytokines (Dasnd Basu, 2007; Goshen et al., 2007), normal aging (Kuhn et al.,996) and activation of the stress-response systems (Joca et al.,007; Karten et al., 2005). On the other hand, physical activity (vanraag et al., 1999) and mood stabilizers such as lithium can promoteeurogenesis (Chen et al.). Many treatment benefits are thought toepend on the release of neurotrophic factors.

Neurotrophins, notably BDNF, have been considered one of theost important mediators of synaptic plasticity and apoptosis con-

rol in mood disorders. Individuals with BD, when compared withealthy controls, have lower peripheral levels of BDNF in mania and

n depressive episodes, as described by a systematic review, with meta-regression analysis (Fernandes et al., 2011). In that study,DNF levels in euthymia were unaltered, although they were influ-nced by age and length of illness. A separate study reported thatDNF levels were decreased in euthymic individuals, but only inhe latter stages of illness (Kauer-Sant’Anna et al., 2009). Therefore,DNF has been considered both a marker of clinical symptoms and

mechanism underlying neuroprogression (Berk, 2009; Berk et al.,010).

Interestingly, reduced BDNF levels have also been found inging (Perovic et al., 2012). In non-demented elderly individuals,ower BDNF plasma levels have been correlated with white-mattertrophy (Driscoll et al., 2012). The age-related decline in BDNF

Please cite this article in press as: Rizzo, L.B., et al., The theory of bipclinical care and research. Neurosci. Biobehav. Rev. (2014), http://dx.d

s probably due to epigenetic changes. In one rodent study, hip-ocampal BDNF mRNA was lower in 12-month-old compared with

months old animals. In addition, there was a decrease in thexpression of TrkB, the BDNF receptor mediating neuroprotection

PRESSvioral Reviews xxx (2014) xxx–xxx 5

and structural plasticity, which was accompanied by lower levelsof the two main downstream effector kinases, pAkt and proteinkinase C (Perovic et al., 2012). Recently, a post-mortem studyshowed an age-related decrease in BDNF transcripts in amygdalaof both healthy and MDD individuals as well as in BDNF-dependentgene expression. Interestingly, most genes that are age-dependentin control subjects display greater age effects in MDD subjects(Douillard-Guilloux et al., 2013).

A second neurotrophin likely to be of importance to mood dis-orders, and particularly in senescence processes, is insulin-likegrowth factor 1 (IGF-1). In mouse behavioral studies, experimen-tal IGF-1 deficiency induces depressive-like symptoms (Mitschelenet al.), and in an inflammatory depression model, IGF-1 reduceddepression-like behavior (Park et al.). Polymorphisms in the IGF-1gene have been associated with BD, suggesting that genomic vari-ants may increase susceptibility (Pereira et al.). Insulin-like growthfactor-1 (IGF-1) can increase neural stem cell proliferation in thedentate gyrus of the hippocampus and increase CA1 pyramidalneuron dendritic spine density (Glasper et al.). IGF-1 activates anti-apoptotic signaling, protecting neurons against oxidative stress(Floratou et al.; Wang et al.). Moreover, a recent study found that BDpatients who respond to lithium express greater amounts of IGF-1(Squassina et al.) compared to non-responders. The IGF-1 systemis a well-known regulator of aging; however, the relationship maybe complex and the overall effect on lifespan may depend on theperiod of reduced IGF-1 signaling (Kenyon). In animals, the IGF-1receptor determines lifespan based on a neuroendocrine mecha-nism during normal development that increases metabolic functionand reduces longevity (Holzenberger et al.). In humans, mutationsthat decrease the function of the IGF-1 receptor or of signalingmolecules downstream of the IGF-1 receptor are associated withlongevity (Kenyon). However, plasma IGF-1 concentrations declinewith age and they are negatively associated with cardiometabolicrisk factors such as BMI, insulin resistance and blood pressure, sug-gesting that concentrations of IGF-1 may be a marker of metabolicdisease rendering patients with BD more susceptible to neuralinsult and impaired resilience (Sesti et al.). In later-life and in mooddisorders, increases in oxidative stress, apoptosis, inflammation,and declining endothelial function may be ameliorated by IGF-1(Higashi et al.). Further investigation into the relationships betweenBD, aging and the IGF-1 system are warranted.

2.4.3. Short telomeresIn humans and other animals, cellular senescence has been

attributed mainly to the shortening of telomeres. Telomeres arespecialized structures present at the end of chromosomes com-posed by DNA tandem repeats of (TTAGGG/CCCTAA)n ranging5–15 kbp (Aubert and Lansdorp, 2008) and proteins such as TRFs,POT, TIN2, which stabilize the region (Amiard et al., 2007; Teixeiraet al., 2004). Telomeres are believed to have evolved to “cap” chro-mosomal termini and prevent end-to-end recombination and thusserve a critical role in the maintenance of chromosomal integrity(Blackburn, 2001; Blackburn et al., 2000; Simon et al., 2006). Sincetelomerase levels are insufficient in normal human cells, in each celldivision telomeres get shorter due to the “end replication problem”.When telomeres become too short, the cell ceases to proliferate andenters a state known as “replicative senescence”. Thus, meteredloss of telomeres can serve as a cellular “mitotic clock” that ulti-mately limits the number of cell divisions and cellular life span.For instance, telomere length declines in stem cells, affecting theirfunctionality and capability to generate new cells (Vaziri et al.,1994). Interestingly, shorter telomeres have been associated with

olar disorder as an illness of accelerated aging: Implications foroi.org/10.1016/j.neubiorev.2014.02.004

higher risk of mortality due to cardiovascular and infection-relateddiseases (Cawthon et al., 2003). Although the replicative problemplay a role in telomere shortening, other mechanisms are involvedlike oxidative stress (von Zglinicki, 2000).

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6 L.B. Rizzo et al. / Neuroscience and Biobehavioral Reviews xxx (2014) xxx–xxx

Fig. 1. Biological findings linking bipolar disorder and aging. White matter hyperintensities (WMH), T regulatory cells (Treg), cytomegalovirus (CMV), nitric Oxide (NO),t ase (C

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hiobarbituric acid reactive substances, (TBARS), superoxide dismutase (SOD), catal

A preliminary study conducted by Simon and collaboratorsound reduction of telomere length from peripheral leukocytes inndividuals with mood disorders (MDD and BD) compared withealthy controls (Simon et al., 2006). Hartman et al. also foundhorter mean telomere length in leukocytes of individuals withDD compared to healthy controls, although the duration of ill-

ess and depression severity were not associated with telomereength (Hartmann et al., 2010). On the other hand, the numberf previous depressive episodes was an important determinant ofelomere shortening in another study (Wolkowitz et al., 2011). Inddition, pre-treatment telomerase activity was significantly ele-ated in depressed individuals compared with healthy controls andelomerase activity was correlated with depression severity andredicticting response to antidepressant treatment (Wolkowitzt al., 2012).

Telomere shortening is less investigated in BD than in MDD. In aroup of individuals with BD type 2, short telomeres were moreommon among the affected group that among healthy controlubjects (15.04% vs. 13.48%; p = 0.04). Mean telomere length in theatient group was 552 base pairs (bp) shorter than in the controlroup; however, the difference did not reach statistical significanceElvsashagen et al., 2011). The effect of lithium in telomere lengthf individuals with BD was also investigated. Lithium-treated BDatients had 35% longer telomeres compared with healthy controls.

n this study, telomere length correlated positively with lithiumreatment duration of >30 months and was negatively associatedith increasing number of depressive episodes. Thus, response to

ithium in BD patients may also be associated with longer telomeres

Please cite this article in press as: Rizzo, L.B., et al., The theory of bipclinical care and research. Neurosci. Biobehav. Rev. (2014), http://dx.d

Martinsson et al., 2013).Possible causes for shortening of telomeres have been investi-

ated. One study assessing telomere length in the cerebellar grayatter of patients diagnosed with MDD, BD and schizophrenia

AT).

found no difference in mean telomere length between the threegroups and controls. Since mean telomere length has been reportedto be a heritable quantitative trait, the authors also carried outgenome-wide mapping of genetic factors for telomere length andno association survived correction of multiple comparisons for thenumber of SNPs studied. This suggests that genetic predispositionto shorter telomere length could be determined by multiple lociwith small effect sizes (Zhang et al., 2010).

Although a cause-effect relationship cannot be definitivelyestablished, stress and its impact in the organism have been postu-lated as an important factor. In subjects with MDD, telomere lengthwas inversely correlated with oxidative stress and with inflamma-tion in depressed individuals (Wolkowitz et al., 2011). In addition,stress is implicated as a crucial causal mechanism for mood disor-ders, as well as for aging. In one study of individuals with MDD,short telomere length was associated with Perceived Stress Ques-tionnaire scores, and with a hypocortisolemic state, which wasespecially prevalent among patients with a high familial loadingof affective disorders and high levels of C-reactive protein levels(Wikgren et al., 2012).

A possible limitation of current research investigating telom-eres in mood disorders is the possibility of tissue-specific changes.It is possible that premature senescence may occur particularly inrapidly dividing tissues such as leukocytes, sparing others such asthe cerebellar gray matter, as suggested by Zhang and collaborators.Analyses that include other brain regions, particularly the sub-granular zone of the dentate gyrus or the subventrical zone whereneurogenesis continues into adulthood may be more appropriate.

olar disorder as an illness of accelerated aging: Implications foroi.org/10.1016/j.neubiorev.2014.02.004

Additionally, analyses that seek to identify correlations betweenother peripheral senescence-related biomarkers with telomerelength and clinical symptoms or staging in BD are also warranted Q3(Fig. 1).

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Fig. 2. The relation between Allostatic Load (AL) and Accelerated Aging (AA)hypotheses. Both hypotheses are complementary, the higher the allostatic loadexperienced by BD patients, the higher will the demand of mechanisms to recoverhomeostasis. This leads to an exhaustion of the entire system and promotes theaccelerated aging. The AA paradigm expands the AL hypothesis to its long termconsequences, but also offers new insights into the etiopathology of BD, putting inperspective some of the current knowledge and indicating new areas for furtherrg

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and interaction with GSK-3 and Bcl-2 (Lai et al., 2006).

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esearch. AA hypothesis also opens the field on thinking BD as not just a neuropro-ressive, but a somatoprogressive disorder.

. Implications for research directed to clinical care

Bipolar disorder is a complex disease, accumulating evidenceoints to the involvement of a myriad of pathophysiological path-ays that are dynamic and interact with each other and with

he environment. Notwithstanding these foraging observations, unitary disease model is still unavailable, necessitating furtherdvancement of our understanding of this multifaceted mentalisorder, and the development and refinement of comprehensiveheoretical frameworks.

One integrative hypothesis for neuroprogression in BD is thellostatic Load (AL) which says that BD patients are under stress-

ul conditions (cyclic mood episodes, drug addiction and otheromorbidities) and struggle to restore homeostasis by allostaticechanisms. In the same way, aging can be thought as a loss in

he capability to reattain homeostasis (O’Neill, 1997). In this con-ept, the AA and AL hypotheses are complementary (Fig. 2), theurden of BD promotes exhaustion of allostatic mechanisms thatromote homeostasis. The AA paradigm expands the AL hypothe-is to its long term consequences, but also offer new insights intohe etiopathology of BD, putting in perspective some of the cur-ent knowledge and indicating new areas for further research. AAypothesis also opens the field on thinking BD as not just a neuro-rogressive, but a somatoprogressive disorder.

Although the most explored models for progression of BD areelated to stress, it is intuitive that, even organisms that are notubmitted to chronic stress will age. In addition to environmen-al agents, there is also a strong genetic component in aging.ne interesting insight about genetic component in aging can bebtained from diseases marked by a highly accelerated aging, suchs Hutchinson-Gilford Progeria (HGP) and Werner syndrome (WS)Hegele, 2003; Heyn et al., 2013). As naturally aged individuals, HGPnd WS patients present hair graying, skin thinning, atherosclero-is and osteopenia. Genetically, the disease could be traced backo mutations in lamin A (LMNA) (De Sandre-Giovannoli et al., 2003;riksson et al., 2003; Worman and Bonne, 2007) and the Werneryndrome RecQ helicase like (WRN) (Yu et al., 1996) genes. Althoughimilarities between these conditions and BD were never explored,chizophrenia was conceptualized by some authors as a segmen-

Please cite this article in press as: Rizzo, L.B., et al., The theory of bipclinical care and research. Neurosci. Biobehav. Rev. (2014), http://dx.d

al Progeria, due to similarities in genetic and epigenetic controlf CNS senescence between the disorders (Papanastasiou et al.,011).

PRESSvioral Reviews xxx (2014) xxx–xxx 7

From a clinical point of view, based on the evidence of the pro-gressive nature of BD, some authors propose that the notion ofclinical staging can be applied to BD (Kapczinski et al., 2009; Scottet al., 2013). The main benefits are allowing better prognosis andmore personalized treatments. The use of biomarkers, includingneurotrophins, inflammatory markers and oxidative stress mark-ers have been proposed as auxiliary tools to refine the descriptionof the stages (Kapczinski et al., 2009). In this sense, age-relatedfeatures, such as the presence of medical comorbidities, cognitiveimpairment and shortened telomere length could be useful in thecharacterization of clinical stages. Also, investigation of the pro-gression of these features along the course of the disease may allowearly interventions aimed at better management and prognoses forpatients.

Finally, the recognition of aging processes as part of the BD puz-zle leads to the possibility of treatments targeting specifically thesepathways the so-called “anti-aging” strategies, including nutri-tional approaches and pharmacological and non-pharmacologicalinterventions

3.1. Pharmacological strategies

3.1.1. Current pharmacology modulating aging relatedmechanisms

The mechanisms of action of drugs currently used to treat BD isnot completely understood, but there are some data showing theircapability to modulate pathways related to aging. Patients in treat-ment with lithium show reduced neuronal loss and higher level ofN-acetyl-aspartate (NAA) (marker of neuronal viability) (Beardenet al., 2007; Moore et al., 2000), suggesting a neuroprotectionaleffect by lithium which is already known to be partially mediatedby several mechanisms, its capability to reduce glutamate-inducedexcitotoxicity by NMDA receptors (Hashimoto et al., 2002), directand indirect inhibittion of the pro-apoptotic protein Glycogen syn-thase kinase 3 (GSK-3) (Chiu and Chuang, 2011; Stambolic et al.,1996), induction the antiapoptotic protein B-cell lymphoma 2 (Bcl-2) (Chen and Chuang, 1999) and induction of the growth factorsBDNF (Fukumoto et al., 2001) and vascular endothelial growth fac-tor (VEGF) (Guo et al., 2009).

Over the last years, GSK-3 was also identified as a regulator ofmany components of the immune system. GSK-3 plays an impor-tant role in the signal transmission to promote production of thepro-inflammatory cytokines IL-6, IL-1�, IL-12p40, IFN� and TNF-�and inhibition of the anti-inflammatory cytokine IL-10 and IL1-RA(Beurel et al., 2010). The inhibition of GSK-3 by lithium and itsconsequent impact in the immune system may be one of the ther-apeutic mechanisms of lithium. Recently, the recognition that BDpatients that were lithium intakers had longer telomeres raised thequestion by which means lithium could promote telomere exten-sion. It seems to be also related to the inhibition of GSK-3 andconsequently promoting the transcription hTERT the catalytic sub-unit bearing the enzymatic activity of telomerase (Martinsson et al.,2013).

Lithium also seems to plays a role in the reduction of oxida-tive stress, since lithium treated patients present lower peripherallevels of oxidative stress makers like TBARS, SOD and CAT com-pared to unmedicated patients (Machado-Vieira et al., 2007). Also,lithium pré-treatment was able to protect human neuroblastoma(SH-SY5Y) cell line from rotenone and H2O2-induced cytotoxicity(Lai et al., 2006). The mechanism by which the medication medi-ates oxidative protection is not yet completely understood, but itis partly due to induction of antioxidant proteins like CAT and SOD,

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Valproic acid (VPA) also inhibits GSK-3 activity, although itis now clear yet if it shares the same direct effect as lithiumor other mechanism are involved (Chen et al., 1999; Rosenberg,

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007). VPA also impacts in the immunological system promot-ng anti-inflammatory effects in different models as ischemia andxperimental auto-immune neuritis reducing pro-inflammatoryytokines IFN-�, TNF-�, IL-1, IL-6 and IL-17, and also elevating lev-ls of Treg cell (Zhang et al., 2008; Zhang et al., 2012). Mechanismsy which VPA promotes the anti-inflammatory effect needs to belarified, but it seems to be partly mediated by inhibition of GSK-

and histone deacetylase inhibition (Beurel et al., 2010; Grabiect al., 2011). The relation between GSK-3 inhibition by VPA andnduction of hTERT transcription still needs to be investigated. VPAnd atypical antipsychotics also seems to promote effect on cellurvival by elevating levels BDNF and fibroblast growth factor 1FGF1)(Bai et al., 2003; Kao et al., 2013; Yasuda et al., 2009) andpregulating Bcl-2 (Bai et al., 2004).

.1.2. Sirtuins as possible new targetThe sirtuins are a family of ribosyltransferase or deacylase

nzymes that influence a plethora of processes involved in aging,ncluding apoptosis, DNA repair, the inflammatory response andesistance to stress. The mammalian sirtuin homologues, SIRTs–7, are also involved in energy metabolism, with a particularole in metabolic efficiency and maintenance of function duringow energy situations. The sirtuin genes can be upregulated byalorie restriction, with longevity promoting effects (Kanfi et al.,012). For example, SIRT6 is expressed in the nucleus where it

s involved in DNA repair, regulating cell metabolism, and regu-ating the secretion of TNF. In male mice, over-expression of Sirt6ncreases lifespan and alters IGF-1 signaling, consistent with a rolef IGF-1 in determining longevity (Kanfi et al., 2012). On the otherand, SIRT6 deficiency leads to enhanced NF-�B dependent sig-aling, apoptosis and accelerated cell senescence (Kawahara et al.,009).

Recently, decreased expression of SIRT1, SIRT2 and SIRT6 wasound in white blood cells collected from BD patients in states ofcute depression compared to controls. In contrast, SIRT mRNA lev-ls in euthymic BD patients were different from those of controlsAbe et al., 2011), suggesting that sirtuin genes may be defi-iently expressed in BD, and that sirtuin expression may be a statearker of illness. Previously, differences have been described in

he response of white blood cells to glucose deprivation betweenD subjects and controls – whereas healthy controls showed up-egulated transcripts related to mitochondrial energy metabolism,hese transcripts were down-regulated in BD (Naydenov et al.,007). Sirtuin expression would seem to be a compensatory pro-ective measure, and this resilience pathway may be defective inD.

These observations suggest the possibility for novel pharmaco-ogical interventions. For instance, in animal models, resveratrolan activate SIRT1, prolonging the lifespan in obese animalsnd reversing age-related cardiovascular dysfunction (Alcain andillalba, 2009; Barger et al., 2008). More potent pharmacologicalctivators of SIRT1 are under development. These agents can moreramatically increase mitochondrial activity (Alcain and Villalba,009). Interestingly, sirtuin activity is inhibited by nictotinamide,

final product of the kynurenine pathway and an important com-onent of NAD and NADPH involved in the mitochondrial electronransport chain. It has been suggested that blocking nicotinamideinding to its cognate receptors could enhance sirtuin activity andrevent tissue damage caused by age-related degenerative diseasesuch as diabetes, Alzheimers and atherosclerosis (David Adams

Please cite this article in press as: Rizzo, L.B., et al., The theory of bipclinical care and research. Neurosci. Biobehav. Rev. (2014), http://dx.d

nd Lori, 2007; Milne et al., 2007). These pharmacological strate-ies might be useful to mitigate the cellular damage that occursuring depressive episodes, and prevent the associated neuropro-ression.

PRESSvioral Reviews xxx (2014) xxx–xxx

3.2. Non-pharmacological strategies

3.2.1. Physical activityPhysical activity and cardiopulmonary fitness are well-

documented neuroprotective strategies that can increase brainvolumes (Colcombe et al., 2006; Colcombe et al., 2006) and pre-serve cognitive function later in life (Barnes et al., 2003) evenin groups of patients with concomitant cardiovascular morbidity(Swardfager et al., 2010a) or clinical mild cognitive impairment(Baker et al., 2010). It has been suggested that these effects may bemediated, in part by augmentation of neurotrophin concentrations(e.g. BDNF and IGF-1) (Erickson et al., 2011; Llorens-Martin et al.,2010; Swardfager et al., 2011) but improvements in other aspects ofphysiological function may also ameliorate neurocognitive decline,including improvements in vascular endothelial function (Banket al., 1998; Fuchsjager-Mayrl et al., 2002; Xiang et al., 2009). Vas-cular endothelial dysfunction is related to increased generationof oxidative species, which can irreversibly damage intracellularcomponents of the cerebral neurovascular unit and compromiseregulation of cerebral blood flow and thus brain function. Vascu-lar endothelial cell senescence and changes in vascular endothelialfunction occur with aging, favoring pro-inflammatory and pro-oxidant processes that may contribute substantially to age-relatedneurological decline (Yildiz, 2007), particularly since these pro-cesses are exacerbated by age-related cognitive risk factors suchas diabetes and hypertension.

Physical activity is also known to increase telomerase activityboth in human and animal models (Ludlow et al., 2012; Werneret al., 2008; Wolf et al., 2011). Telomerase has not yet been eval-uated in BD, but there are reports of decreased activity in majordepression and schizophrenia (Porton et al., 2008; Wolkowitz et al.,2012). These data suggest that BD may follow the same direction,and other mechanism by which patients could be benefited by exer-cise.

The extant literature suggests that BD, and manic or hypo-manic symptoms in particular, may be associated with prematureincreases in vascular endothelial dysfunction (Fiedorowicz et al.,2012; Rybakowski et al., 2006). Physical activity as a means to pro-mote vascular endothelial health or telomere length in BD has notyet been assessed; however, poorer physical fitness can confer anincreased risk of affective disorders including BD (Aberg et al., 2012)and exercise has been suggested as a strategy to improve cognitionin BD (Ng et al., 2007). Prospective controlled studies are needed,and related mechanisms require further investigation (Kucyi et al.,2010).

4. Conclusions

There is considerable overlap between neurobiological charac-teristics of BD and processes of both normal and pathological aging,which is evident in clinical, physiological, neurostructural, cellular,and molecular studies. The strengths of the AA integrative view ofBD progression are that the hypothesis comprises and also expendsthe neuroprogression and allostatic load view, also expands thefield of possible biological mechanisms involved in the pathophys-iology of the disease. The AA hypothesis also creates a theoreticalframework that encompasses not only neurological but also sys-temic alterations involved in the pathophysiology of BD.

Although AA hypothesis integrates the current knowledgeregarding progression of BD, it does not provide direct answersabout the mechanisms that generate mood cyclicity. Yet, in

olar disorder as an illness of accelerated aging: Implications foroi.org/10.1016/j.neubiorev.2014.02.004

our concept, mood cyclicity generates stressful conditions thatdemand the action of biological mechanisms to reattain homeo-stasis, the chronicity of this conditions could promote acceleratedaging (Fig. 2). Other limitation is that albeit there are compelling

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ata supporting AA hypothesis, most studies use cross-sectionalethodology which are more susceptible to bias.The present work, creates the basis for new prospective studies

ocusing on AA framework and consequently bring more under-tanding about BD etiology and physiology. Although the scope ofhe present work made an in deep analysis of AA in BD, there areome data suggesting that this concept could be extrapolated forther psychiatric disorders like major depression, schizophreniand posttraumatic stress disorder (Simon et al., 2006; Wolkowitzt al., 2010).

Finally, the exploration of physiological processes involved inging provides useful insights into the biology of BD, and newotential to suggest new avenues of treatment. Notwithstanding,he associated of controversy and practical challenges, anti-agingnterventions could be beneficial in subpopulations of BD warrant-ng further investigation.

onflict of interest statement

The authors declare that they have no competing financial inter-sts.

ncited references

Chen et al., 2000, Elkind et al., 2010, Floratou et al., 2012, Glaspert al., 2010, Higashi et al., 2012, Holzenberger et al., 2003, Katant al., 2013, Kelley et al., 2013, Kenyon, 2010, Mitschelen et al., 2011,ark et al., 2011, Pereira et al., 2011, Sesti et al., 2005, Squassinat al., 2013, Swardfager and Black, 2013 and Wang et al., 2010.

cknowledgements

The authors acknowledge support by fellowships from Coor-ination of Improvement of Higher Education Personnel (CAPES),ational Counsel of Technological and Scientific Development

CNPq) and São Paulo Research Foundation (Fapesp).Dr. Swardfager acknowledges support by fellowships from the

eart & Stroke Foundation Centre for Stroke Recovery and theoronto Rehabilitation Institute.

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