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.
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.
|Chen, Stephen H; Epel, Elissa S; Mellon, Synthia H et al. (2014) Adverse childhood experiences and leukocyte telomere maintenance in depressed and healthy adults. J Affect Disord 169:86-90|
|Lindqvist, Daniel; Mueller, Susanne; Mellon, Synthia H et al. (2014) Peripheral antioxidant markers are associated with total hippocampal and CA3/dentate gyrus volume in MDD and healthy controls-preliminary findings. Psychiatry Res 224:168-74|
|Epel, Elissa S; Lithgow, Gordon J (2014) Stress biology and aging mechanisms: toward understanding the deep connection between adaptation to stress and longevity. J Gerontol A Biol Sci Med Sci 69 Suppl 1:S10-6|
|Rawdin, B J; Mellon, S H; Dhabhar, F S et al. (2013) Dysregulated relationship of inflammation and oxidative stress in major depression. Brain Behav Immun 31:143-52|
|Wolkowitz, O M; Mellon, S H; Epel, E S et al. (2012) Resting leukocyte telomerase activity is elevated in major depression and predicts treatment response. Mol Psychiatry 17:164-72|
|Wolkowitz, Owen M; Mellon, Synthia H; Epel, Elissa S et al. (2011) Leukocyte telomere length in major depression: correlations with chronicity, inflammation and oxidative stress--preliminary findings. PLoS One 6:e17837|
|Jeste, Dilip V; Wolkowitz, Owen M; Palmer, Barton W (2011) Divergent trajectories of physical, cognitive, and psychosocial aging in schizophrenia. Schizophr Bull 37:451-5|
|Wolkowitz, Owen M; Reus, Victor I; Mellon, Synthia H (2011) Of sound mind and body: depression, disease, and accelerated aging. Dialogues Clin Neurosci 13:25-39|
|Wolkowitz, Owen M; Wolf, Jessica; Shelly, Wendy et al. (2011) Serum BDNF levels before treatment predict SSRI response in depression. Prog Neuropsychopharmacol Biol Psychiatry 35:1623-30|