Major depression, a disease affecting up to 16% of the population at some point in their lives, has been likened to a state of """"""""accelerated aging,"""""""" with an increased risk of acquiring certain diseases of aging, such as immune function impairment, cardiovascular disease and dementia. Depression may also be associated with accelerated aging at the level of the individual cell. The biological mechanisms underlying such cellular vulnerability and increased risk of co-morbid diseases remain unknown. We will explore a model in which depression-associated oxidative stress and inflammatory stress are related to accelerated aging in two model systems, one peripheral and one central. Specifically, we will assess whether: (1) telomeres are shortened in the DNA of peripheral blood mononuclear cells (PBMC's) of depressed individuals;(2) hippocampal (total and subfield) volumes are decreased in depressed individuals;and (3) accelerated aging in both of these systems is mediated by increased oxidative stress and pro-inflammatory cytokine activity. Our preliminary data suggest that PBMC telomeres are shortened in depressed individuals, especially those with longer durations of untreated depression, representing between 8-9 years of accelerated biological aging. In non-depressed populations, short PBMC telomeres have been related to significant medical morbidity and early mortality, raising the possibility that our observed changes in PBMD telomere length in depression contributes to medical morbidity in these individuals. Our preliminary neuroimaging data, while limited by small sample sizes, suggest diminished volume of the hippocampus, and of the CA3/dentae gyrus subfield, in particular, the region involved in neurogenesis. Importantly, our preliminary data also suggest that PBMC telomere length and hippocampal volume are both inversely correlated with oxidative and inflammatory stress. This raises the possibility of conjoint peripheral-central accelerated aging processes in depression, with similar biochemical mediators underlying both. Our primary aims are to determine whether PBMC telomere shortening and hippocampal volume loss occur in major depression, whether oxidative and inflammatory stress are increased in major depression, and whether these putative biochemical mediators of accelerated aging are correlated with our outcome measures. To accomplish this, 82 un-medicated depressed subjects and 82 matched controls will have PBMC's assayed for telomere length, and a subset of 55 un-medicated depressed subjects and 55 matched controls will additionally undergo ultra-high resolution brain MRI scans to assess hippocampal and hippocampal subfield volumes. All subjects will have serum and urine assayed for putative biochemical mediators. Path analysis will determine whether these biochemical levels mediate the relationship between depression and PBMC telomere length and hippocampal volume. Discovering fundamental changes in telomere cell biology and in hippocampal aging will advance our understanding of the pathophysiology of major depression and of its medical co-morbidities, and will present new targets for prevention and treatment.

Public Health Relevance

Major depression is among the leading causes of disability worldwide, causing psychological, occupational and social disability, and it is associated with significantly higher rates of serious age- related physical illnesses. The goal of this study is to explore a new theory - that depression is associated with premature aging of certain cells in the body, both in the peripheral blood stream and in the central nervous system, that this is traceable to specific biochemical mediators, and that this may account for some of the disability associated with depression. This in turn would yield new insights into the biology of depression and might spur the development of new treatments aimed at the molecular causes and consequences of depression.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
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Evans, Jovier D
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Wolkowitz, Owen M (2018) Accelerated biological aging in serious mental disorders. World Psychiatry 17:144-145
Lindqvist, Daniel; Wolkowitz, Owen M; Picard, Martin et al. (2018) Circulating cell-free mitochondrial DNA, but not leukocyte mitochondrial DNA copy number, is elevated in major depressive disorder. Neuropsychopharmacology 43:1557-1564
Fair, Brittany; Mellon, Synthia H; Epel, Elissa S et al. (2017) Telomere length is inversely correlated with urinary stress hormone levels in healthy controls but not in un-medicated depressed individuals-preliminary findings. J Psychosom Res 99:177-180
Hough, Christina M; Lindqvist, Daniel; Epel, Elissa S et al. (2017) Higher serum DHEA concentrations before and after SSRI treatment are associated with remission of major depression. Psychoneuroendocrinology 77:122-130
Steenkamp, Lisa R; Hough, Christina M; Reus, Victor I et al. (2017) Severity of anxiety- but not depression- is associated with oxidative stress in Major Depressive Disorder. J Affect Disord 219:193-200
Lindqvist, Daniel; Dhabhar, Firdaus S; James, S Jill et al. (2017) Oxidative stress, inflammation and treatment response in major depression. Psychoneuroendocrinology 76:197-205
Jin, Rowen O; Mason, Sara; Mellon, Synthia H et al. (2016) Cortisol/DHEA ratio and hippocampal volume: A pilot study in major depression and healthy controls. Psychoneuroendocrinology 72:139-46
Darrow, Sabrina M; Verhoeven, Josine E; Révész, Dóra et al. (2016) The Association Between Psychiatric Disorders and Telomere Length: A Meta-Analysis Involving 14,827 Persons. Psychosom Med 78:776-87
Mellon, S H; Wolkowitz, O M; Schonemann, M D et al. (2016) Alterations in leukocyte transcriptional control pathway activity associated with major depressive disorder and antidepressant treatment. Transl Psychiatry 6:e821
Hough, Christina M; Bersani, F Saverio; Mellon, Synthia H et al. (2016) Leukocyte telomere length predicts SSRI response in major depressive disorder: A preliminary report. Mol Neuropsychiatry 2:88-96

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