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

Rizzo, Lucas Bortolotto; Costa, Leonardo Gazzi; Mansur, Rodrigo B.; Swardfager, Walter; Belangero, Síntia Iole; Grassi-Oliveira, Rodrigo; McIntyre, Roger S.; Bauer, Moisés E.; Brietzke, Elisa

doi:10.1016/j.neubiorev.2014.02.004

Cited by 183Bipolar Disorder and TreatmentTreatment of Major DepressionSchizophrenia research and treatment

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

Rizzo, Lucas Bortolotto, Costa, Leonardo Gazzi, Mansur, Rodrigo B., Swardfager, Walter, Belangero, Síntia Iole, Grassi-Oliveira, Rodrigo, McIntyre, Roger S., Bauer, Moisés E. +1 more·2014·Neuroscience & Biobehavioral Reviews

DOI 10.1016/j.neubiorev.2014.02.004

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Abstract

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 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 understood 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 senescence 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.

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Bipolar disorder may also be characterized by 'accelerated aging'.
“Bipolar disorder (BD) may also be characterized by “accelerated aging” (Rizzo et al., 2014; Sodhi et al., 2012; Yatham et al., 2009 (but see Gildengers et al., 2013)).”
From Psychiatric disorders and leukocyte telomere length: Underlying mechanisms linking mental illness with cellular aging (2015) · cites this paper as Rizzo et al., 2014

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Infectious Burden and Carotid Plaque Thickness
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Cingulate White Matter Neurons in Schizophrenia and Bipolar Disorder
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Bipolar Disorder and Metabolic Syndrome: A Systematic Review
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Perović, M., Tešić, V., Mladenović, A., Smiljanić, K., Lončarević‐Vasiljković, N., Ruždijić, S., & Kanazir, S. (2012) · AGE · doi:10.1007/s11357-012-9495-6 · Cited by 81 · see citing works
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Squassina, A., Costa, M. F., Congiu, D., Manchia, M., Angius, A., Deiana, V., Ardau, R., Chillotti, C., Severino, G., Calza, S., et al. (2013) · Pharmacological Research · doi:10.1016/j.phrs.2013.04.004 · Cited by 80 · see citing works
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Chronic Exercise Modifies Age-Related Telomere Dynamics in a Tissue-Specific Fashion
Ludlow, A. T., Witkowski, S., Marshall, M. R., Wang, Z. J., Lima, L., Pitchford, L. M., Spangenburg, E. E., & Roth, S. M. (2012) · The Journals of Gerontology Series A · doi:10.1093/gerona/gls002 · Cited by 77 · see citing works
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Rosa, A. R., Reinares, M., Amann, B. L., Popović, D., Franco, C., Comes, M., Torrent, C., Bonnín, C. D. M., Solé, B., Valentí, M., et al. (2011) · Bipolar Disorders · doi:10.1111/j.1399-5618.2011.00964.x · Cited by 74 · see citing works
Immunosenescence is associated with human cytomegalovirus and shortened telomeres in type I bipolar disorder
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Valproic acid attenuates inflammation in experimental autoimmune neuritis
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Geroprotectors as a novel therapeutic strategy for COPD, an accelerating aging disease
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Insulin-like growth factor-I peptides act centrally to decrease depression-like behavior of mice treated intraperitoneally with lipopolysaccharide
Park, S.-E., Lawson, M. A., Dantzer, R., Kelley, K. W., & McCusker, R. H. (2011) · Journal of Neuroinflammation · doi:10.1186/1742-2094-8-179 · Cited by 65 · see citing works
A Randomized, Double-blind, Placebo Controlled-trial of Triflusal in Mild Cognitive Impairment
Gómez‐Isla, T., Blesa, R., Boada, M., Clarimón, J., del Ser, T., Domènech, G., Ferro, J. M., Gómez‐Ansón, B., Manubens, J. M., Martínez‐Lage, J. M., et al. (2008) · Alzheimer Disease & Associated Disorders · doi:10.1097/wad.0b013e3181611024 · Cited by 64 · see citing works
Insulin dysfunction and allostatic load in bipolar disorder
Brietzke, E. M., Kapczinski, F. P., Grassi‐Oliveira, R., Grande, I., Vieta, E., & McIntyre, R. S. (2011) · Expert Review of Neurotherapeutics · doi:10.1586/ern.10.185 · Cited by 64 · see citing works
Differential neuroendocrine and immune responses to acute psychosocial stress in women with type 1 bipolar disorder
Wieck, A., Grassi-Oliveira, R., do Prado, C. H., Rizzo, L. B., de Oliveira, A. S., Kommers-Molina, J., Viola, T. W., Teixeira, A. L., & Bauer, M. E. (2013) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2013.07.005 · Cited by 63 · see citing works
Aerobic Physical Exercise as a Possible Treatment for Neurocognitive Dysfunction in Bipolar Disorder
Kucyi, A., Alsuwaidan, M. T., Liauw, S. S. L., & McIntyre, R. S. (2010) · Postgraduate Medicine · doi:10.3810/pgm.2010.11.2228 · Cited by 62 · see citing works
Anticipated brain molecular aging in major depression
Douillard-Guilloux, G., Guilloux, J.-P., Lewis, D. A., & Sibille, E. (2013) · The American Journal of Geriatric Psychiatry · doi:10.1016/j.jagp.2013.01.040 · Cited by 62 · see citing works
Vasculopathy Related to Manic/Hypomanic Symptom Burden and First-Generation Antipsychotics in a Sub-Sample from the Collaborative Depression Study
Fiedorowicz, J. G., Coryell, W. H., Rice, J. P., Warren, L. L., & Haynes, W. G. (2012) · Psychotherapy and Psychosomatics · doi:10.1159/000334779 · Cited by 61 · see citing works
Insulin-like growth factor 1 protects human neuroblastoma cells SH-EP1 against MPP+-induced apoptosis by AKT/GSK-3β/JNK signaling
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Depression is associated with low plasma Aβ42 independently of cardiovascular disease in the homebound elderly
Qiu, W. Q., Sun, X., Selkoe, D. J., Mwamburi, D. M., Huang, T. L., Bhadela, R., Bergethon, P. R., Scott, T. M., D, P. S. M., Wang, L., et al. (2006) · International Journal of Geriatric Psychiatry · doi:10.1002/gps.1710 · Cited by 60 · see citing works

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Cardiovascular disease in patients with severe mental illness
Nielsen, R. E., Banner, J., & Jensen, S. E. (2021) · Nature Reviews Cardiology · doi:10.1038/s41569-020-00463-7 · Cited by 389 · see citing works
A report on older‐age bipolar disorder from the International Society for Bipolar Disorders Task Force
Sajatovic, M., Strejilevich, S., Gildengers, A. G., Dols, A., Jurdi, R. K. A., Forester, B. P., Kessing, L. V., Beyer, J. L., Manes, F. F., Rej, S., et al. (2015) · Bipolar Disorders · doi:10.1111/bdi.12331 · Cited by 311 · see citing works
Psychiatric disorders and leukocyte telomere length: Underlying mechanisms linking mental illness with cellular aging
Lindqvist, D., Epel, E. S., Mellon, S. H., Penninx, B. W., Révész, D., Verhoeven, J. E., Reus, V. I., Lin, J., Mahan, L., Hough, C. M., et al. (2015) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2015.05.007 · Cited by 285 · see citing works
Bipolar Disorder and Immune Dysfunction: Epidemiological Findings, Proposed Pathophysiology and Clinical Implications
Rosenblat, J., & McIntyre, R. (2017) · Brain Sciences · doi:10.3390/brainsci7110144 · Cited by 258 · see citing works
Is Post-Traumatic Stress Disorder Associated with Premature Senescence? A Review of the Literature
Lohr, J. B., Palmer, B. W., Eidt, C. A., Aailaboyina, S., Mausbach, B. T., Wolkowitz, O. M., Thorp, S. R., & Jeste, D. V. (2015) · American Journal of Geriatric Psychiatry · doi:10.1016/j.jagp.2015.04.001 · Cited by 233 · see citing works
Bipolar depression: the clinical characteristics and unmet needs of a complex disorder
McIntyre, R. S., & Calabrese, J. R. (2019) · Current Medical Research and Opinion · doi:10.1080/03007995.2019.1636017 · Cited by 211 · see citing works
Life expectancy in bipolar disorder
Kessing, L. V., Vradi, E., & Andersen, P. K. (2015) · Bipolar Disorders · doi:10.1111/bdi.12296 · Cited by 218 · see citing works
Causes of decreased life expectancy over the life span in bipolar disorder
Kessing, L. V., Vradi, E., McIntyre, R. S., & Andersen, P. K. (2015) · Journal of Affective Disorders · doi:10.1016/j.jad.2015.03.027 · Cited by 201 · see citing works
Brain structure, cognition, and brain age in schizophrenia, bipolar disorder, and healthy controls
Shahab, S., Mulsant, B. H., Lévesque, M. L., Calarco, N., Nazeri, A., Wheeler, A. L., Foussias, G., Rajji, T. K., & Voineskos, A. N. (2018) · Neuropsychopharmacology · doi:10.1038/s41386-018-0298-z · Cited by 161 · see citing works
Accelerated epigenetic aging and mitochondrial DNA copy number in bipolar disorder
Fries, G. R., Bauer, I. E., Scaini, G., Wu, M., Kazimi, I. F., Valvassori, S. S., Zunta‐Soares, G. B., Walss‐Bass, C., Soares, J. C., & Quevedo, J. (2017) · Translational Psychiatry · doi:10.1038/s41398-017-0048-8 · Cited by 162 · see citing works
Peripheral blood brain-derived neurotrophic factor in bipolar disorder: a comprehensive systematic review and meta-analysis
Munkholm, K., Vinberg, M., & Kessing, L. V. (2016) · Molecular Psychiatry · doi:10.1038/mp.2015.54 · Cited by 157 · see citing works
Areas of uncertainties and unmet needs in bipolar disorders: clinical and research perspectives
Bauer, M., Andreassen, O. A., Geddes, J. R., Kessing, L. V., Lewitzka, U., Schulze, T. G., & Vieta, E. (2018) · The Lancet Psychiatry · doi:10.1016/s2215-0366(18)30253-0 · Cited by 137 · see citing works
Mapping inflammation onto mood: inflammatory mediators of anhedonia
Swardfager, W., Rosenblat, J. D., Benlamri, M., & McIntyre, R. S. (2016) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.02.017 · Cited by 125 · see citing works
Lifespan Gyrification Trajectories of Human Brain in Healthy Individuals and Patients with Major Psychiatric Disorders
Cao, B., Mwangi, B., Passos, I. C., Wu, M., Keser, Z., Zunta‐Soares, G. B., Xu, D., Hasan, K. M., & Soares, J. C. (2017) · Scientific Reports · doi:10.1038/s41598-017-00582-1 · Cited by 124 · see citing works
Sodium Butyrate and Mood Stabilizers Block Ouabain-Induced Hyperlocomotion and Increase BDNF, NGF and GDNF Levels in Brain of Wistar Rats
Varela, R. B., Valvassori, S. S., Lopes-Borges, J., Mariot, E., Dal-Pont, G. C., Amboni, R. T., Bianchini, G., & Quevedo, J. (2015) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2014.11.003 · Cited by 115 · see citing works
Accelerated aging in bipolar disorder: A comprehensive review of molecular findings and their clinical implications
Fries, G. R., Zamzow, M. J., Andrews, T., Pink, O., Scaini, G., & Quevedo, J. (2020) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2020.01.035 · Cited by 110 · see citing works
Neurobiology of bipolar disorders: a review of genetic components, signaling pathways, biochemical changes, and neuroimaging findings
Scaini, G., Valvassori, S. S., Díaz, A. P., Lima, C. N. D. C., Benevenuto, D., Fries, G. R., & Quevedo, J. (2020) · Brazilian Journal of Psychiatry · doi:10.1590/1516-4446-2019-0732 · Cited by 114 · see citing works
Dynamic functional connectivity in bipolar disorder is associated with executive function and processing speed: A preliminary study
Nguyen, T. T., Kovacevic, S., Dev, S. I., Lu, K., Liu, T. T., & Eyler, L. T. (2017) · Neuropsychology · doi:10.1037/neu0000317 · Cited by 109 · see citing works
Severe mental illness: cardiovascular risk assessment and management
Polcwiartek, C., O’Gallagher, K., Friedman, D. J., Correll, C. U., Solmi, M., Jensen, S. E., & Nielsen, R. E. (2024) · European Heart Journal · doi:10.1093/eurheartj/ehae054 · Cited by 104 · see citing works
Are Anxiety Disorders Associated with Accelerated Aging? A Focus on Neuroprogression
Perna, G., Iannone, G., Alciati, A., & Caldirola, D. (2015) · Neural Plasticity · doi:10.1155/2016/8457612 · Cited by 96 · see citing works
Telomere Length, Oxidative Stress, Inflammation and BDNF Levels in Siblings of Patients with Bipolar Disorder: Implications for Accelerated Cellular Aging
Vasconcelos-Moreno, M. P., Fries, G. R., Gubert, C., dos Santos, B. T. M. Q., Fijtman, A., Sartori, J., Ferrari, P., Grün, L. K., Parisi, M. M., Guma, F. T. C. R., et al. (2017) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyx001 · Cited by 92 · see citing works
Five‐year follow‐up of cognitive impairment in older adults with bipolar disorder
Schouws, S. N., Comijs, H. C., Dols, A., Beekman, A. T., & Stek, M. L. (2016) · Bipolar Disorders · doi:10.1111/bdi.12374 · Cited by 90 · see citing works
Accelerated hippocampal biological aging in bipolar disorder
Fries, G. R., Bauer, I. E., Scaini, G., Valvassori, S. S., Walss‐Bass, C., Soares, J. C., & Quevedo, J. (2019) · Bipolar Disorders · doi:10.1111/bdi.12876 · Cited by 85 · see citing works
Brain age in bipolar disorders: Effects of lithium treatment
Gestel, H. V., Franke, K., Petite, J., Slaney, C., Garnham, J. S., Helmick, C. A., Johnson, K., Uher, R., Alda, M., & Hájek, T. (2019) · Australian & New Zealand Journal of Psychiatry · doi:10.1177/0004867419857814 · Cited by 79 · see citing works
Gut microbiome in serious mental illnesses: A systematic review and critical evaluation
Nguyen, T. T., Hathaway, H., Kościółek, T., Knight, R. D., & Jeste, D. V. (2019) · Schizophrenia Research · doi:10.1016/j.schres.2019.08.026 · Cited by 78 · see citing works
Leukocyte telomere length in patients with bipolar disorder: An updated meta-analysis and subgroup analysis by mood status
Huang, Y., Wang, L., Tseng, P., Hung, C., & Lin, P. (2018) · Psychiatry Research · doi:10.1016/j.psychres.2018.09.035 · Cited by 73 · see citing works
Leukocyte telomere length positively correlates with duration of lithium treatment in bipolar disorder patients
Squassina, A., Pisanu, C., Congiu, D., Caria, P., Frau, D. V., Niola, P., Melis, C., Baggiani, G., López, J. P., Cruceanu, C., et al. (2016) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2016.03.020 · Cited by 72 · see citing works
Increased serum levels of eotaxin/CCL11 in late-stage patients with bipolar disorder: An accelerated aging biomarker?
Panizzutti, B., Gubert, C., Schuh, A. L., Ferrari, P., Bristot, G., Fries, G. R., Massuda, R., Walz, J. C., Rocha, N. P., Berk, M., et al. (2015) · Journal of Affective Disorders · doi:10.1016/j.jad.2014.12.010 · Cited by 66 · see citing works
Decelerated epigenetic aging associated with mood stabilizers in the blood of patients with bipolar disorder
Okazaki, S., Numata, S., Otsuka, I., Horai, T., Kinoshita, M., Sora, I., Ohmori, T., & Hishimoto, A. (2020) · Translational Psychiatry · doi:10.1038/s41398-020-0813-y · Cited by 65 · see citing works
Abnormal glycemic homeostasis at the onset of serious mental illnesses: A common pathway
García‐Rizo, C., Kirkpatrick, B. W., Fernández-Egea, E., Oliveira, C., & Bernardo, M. (2016) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2016.02.001 · Cited by 60 · see citing works
Differential mitochondrial DNA copy number in three mood states of bipolar disorder
Wang, D., Li, Z., Liu, W., Zhou, J., Ma, X., Tang, J., & Chen, X. (2018) · BMC Psychiatry · doi:10.1186/s12888-018-1717-8 · Cited by 60 · see citing works
Shortened telomere length in bipolar disorder: a comparison of the early and late stages of disease
Barbé‐Tuana, F. M., Parisi, M. M., Panizzutti, B., Fries, G. R., Grün, L. K., Guma, F. T. C. R., Kapczinski, F. P., Berk, M., Gama, C. S., & Rosa, A. R. (2016) · Brazilian Journal of Psychiatry · doi:10.1590/1516-4446-2016-1910 · Cited by 57 · see citing works
Cerebrospinal fluid oxidative stress metabolites in patients with bipolar disorder and healthy controls: a longitudinal case-control study
Knorr, U. B., Simonsen, A. H., Roos, P., Weimann, A., Henriksen, T., Christensen, E. M., Vinberg, M., Mikkelsen, R. L., Kirkegaard, T., Jensen, R., et al. (2019) · Translational Psychiatry · doi:10.1038/s41398-019-0664-6 · Cited by 57 · see citing works
Increased DNA and RNA damage by oxidation in patients with bipolar I disorder
Jacoby, A. S., Vinberg, M., Poulsen, H. E., Kessing, L. V., & Munkholm, K. (2016) · Translational Psychiatry · doi:10.1038/tp.2016.141 · Cited by 56 · see citing works
Is bipolar disorder associated with accelerating aging? A meta-analysis of telomere length studies
Colpo, G. D., Leffa, D. D., Köhler, C. A., Kapczinski, F. P., Quevedo, J., & Carvalho, A. F. (2015) · Journal of Affective Disorders · doi:10.1016/j.jad.2015.06.034 · Cited by 53 · see citing works
Affective disorders impact prevalence of Flavonifractor and abundance of Christensenellaceae in gut microbiota
Coello, K., Hansen, T. H., Sørensen, N., Ottesen, N. M., Miskowiak, K. W., Pedersen, O. B., Kessing, L. V., & Vinberg, M. (2021) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2021.110300 · Cited by 49 · see citing works
Microbiota abnormalities and the therapeutic potential of probiotics in the treatment of mood disorders
Rios, A. C., Maurya, P. K., Pedrini, M., Zeni‐Graiff, M., Asevedo, E. D. M., Mansur, R. B., Wieck, A., Grassi‐Oliveira, R., McIntyre, R. S., Hayashi, M. A. F., et al. (2017) · Reviews in the Neurosciences · doi:10.1515/revneuro-2017-0001 · Cited by 45 · see citing works
Telomere length in bipolar disorder and lithium response
Squassina, A., Pisanu, C., Corbett, N., & Alda, M. (2015) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2015.10.008 · Cited by 43 · see citing works
Older Age Bipolar Disorder
Dols, A., & Beekman, A. T. F. (2017) · Psychiatric Clinics of North America · doi:10.1016/j.psc.2017.10.008 · Cited by 41 · see citing works
Neuroendocrine and viral correlates of premature immunosenescence
Bauer, M. E., Wieck, A., Petersen, L. E., & Baptista, T. S. A. (2015) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.12786 · Cited by 40 · see citing works
Markers of Inflammation and Monoamine Metabolism Indicate Accelerated Aging in Bipolar Disorder
van den Ameele, S., Fuchs, D., Coppens, V., de Boer, P., Timmers, M., Sabbe, B., & Morrens, M. (2018) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2018.00250 · Cited by 39 · see citing works
Epigenetic GrimAge acceleration and cognitive impairment in bipolar disorder
Lima, C. N. D. C., Suchting, R., Scaini, G., Cuellar, V. A., Favero-Campbell, A. D., Walss‐Bass, C., Soares, J. C., Quevedo, J., & Fries, G. R. (2022) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2022.06.007 · Cited by 37 · see citing works
Cognitive impairment in late life bipolar disorder: Risk factors and clinical outcomes
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Authors: Rizzo, L. B., Costa, L. G., Mansur, R. B., Swardfager, W., Belangero, S. I., Grassi-Oliveira, R., McIntyre, R. S., Bauer, M. E., & Brietzke, E.
Affiliations: Universidade Federal de São Paulo (BR)
University Health Network (CA)
University of Toronto (CA)
Pontifícia Universidade Católica do Rio Grande do Sul (BR)
Corresponding author: Brietzke, Elisa
ORCID: Rizzo, Lucas Bortolotto
Mansur, Rodrigo B.
Swardfager, Walter
McIntyre, Roger S.
Bauer, Moisés E.
Brietzke, Elisa
Venue: Neuroscience & Biobehavioral Reviews
Publisher: Elsevier BV
Published: 2014-05
Volume: 42
Pages: 157-169
ISSN: 0149-7634 (ISSN-L)
DOI: 10.1016/j.neubiorev.2014.02.004
OpenAlex: W2031122384
Cited by: 183
References: 228
Citations by year: 2026: 9 · 2025: 11 · 2024: 14 · 2023: 12 · 2022: 22 · 2021: 6 · 2020: 23 · 2019: 16 · 2018: 14 · 2017: 15 · 2016: 17 · 2015: 18 · 2014: 5
FWCI: 2.52
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Neuroscience & Biobehavioral Reviews (publishedVersion)
PubMed (publishedVersion)
UNIFESP Institutional Repository (Universidade Federal de São Paulo) (submittedVersion)
Funders: Toronto Rehabilitation Institute
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
Topics: Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
Keywords: bipolar disorder, accelerated aging, neuroprogression, immunosenescence, telomere shortening, oxidative stress, amyloid metabolism, brain structural changes, cognitive impairment, successful aging, molecular targets
MeSH terms: Animals, Bipolar Disorder, Brain, Humans, Models, Neurological, Aging, Premature

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

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