Late-life depression is a major public health burden due to its high prevalence and associated morbidity, suicide risk, functional decline, and mortality. Unfortunately, current antidepressant therapies have limited effectiveness; hence, biologically plausible models for new treatments are being pursued. Systemic inflammation is hypothesized to play an important role on the onset and perpetuation of depression, especially in older women. Aging processes involve a heightened inflammatory state, and both inflammatory disorders and depression are more prevalent in women than men. However, increased systemic inflammation does not necessarily lead to depression in all women. Even when robust systemic inflammation is experimentally induced (e.g. endotoxin administration), largely variable increases in depressive symptoms are found. Defining the factors that account for this variability may identify individuals at risk of developing depression when exposed to heightened inflammatory states such as aging, obesity, and chronic disease, and informs future translational studies of depression prevention. In particular, the role of sleep disturbance in explaining this variability requires further attention because it is an independent risk factor for depression and heightens systemic inflammation by increasing the production of proinflammatory cytokines. We have also discovered that women, but not men, who report sleep disturbance including short sleep duration experience significantly more depressive symptoms in response to an inflammatory challenge than women without sleep disturbance. Thus, it is hypothesized that sleep loss is a vulnerability factor for inflammation-induced depressive symptoms in women. However, to date, no experimental approach has been used to evaluate the role of sleep loss on inflammation-induced depressive symptoms. This proposal aims to examine this hypothesis by partial sleep deprivation (PSD) followed by endotoxin challenge in older women. It also aims to explore genomic and socio- emotional mechanisms underlying the association between sleep loss and depressive symptoms. In a randomized controlled factorial design, 80 healthy female volunteers aged 60 to 69 will be randomly assigned to one of 4 arms: 1) uninterrupted sleep followed by placebo; 2) uninterrupted sleep followed by endotoxin; 3) PSD followed by placebo; or 4) PSD followed by endotoxin. Subjects will be administered placebo or endotoxin in the morning after PSD or uninterrupted sleep. Depressive symptoms will be repeatedly assessed over 6 hours after placebo or endotoxin administration. This K23 integrated training and research program is designed to prepare the candidate to become an independent translational investigator in aging research with expertise in epidemiology and psychoneuroimmunology, focused on the identification of multi-level risk factors for and the prevention of late-life depression. For the achievement of this career goal and the completion of the proposed study, the candidate will obtain training in inflammatory biology of depression, aging research, experimental study design, sleep research, and gene expression analysis.

Public Health Relevance

Sleep disturbance and depression in older adults, especially older women, are major public health burdens because both conditions are highly prevalent and associated with morbidity, functional decline, and mortality. Although the association between these two conditions is well known, the mechanisms of this association are poorly understood. The proposed research project aims to examine the potential causal contribution of sleep loss to depressive symptoms via inflammatory mechanisms in older women, by means of experimentally induced sleep deprivation and systemic inflammation. The findings of this study may guide future clinical studies in identifying individuals at risk of developing depression when exposed to heightened inflammatory states such as aging, obesity, and chronic disease and also in developing prevention strategies for late-life depression.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Mentored Patient-Oriented Research Career Development Award (K23)
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Neuroscience of Aging Review Committee (NIA)
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Mackiewicz, Miroslaw
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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Cho, Joshua Hyong-Jin; Olmstead, Richard; Choi, Hanbyul et al. (2018) Associations of objective versus subjective social isolation with sleep disturbance, depression, and fatigue in community-dwelling older adults. Aging Ment Health :1-9
Irwin, Michael R; Cole, Steve; Olmstead, Richard et al. (2018) Moderators for depressed mood and systemic and transcriptional inflammatory responses: a randomized controlled trial of endotoxin. Neuropsychopharmacology :
Cho, Hyong Jin; Savitz, Jonathan; Dantzer, Robert et al. (2017) Sleep disturbance and kynurenine metabolism in depression. J Psychosom Res 99:1-7
Cho, H J; Eisenberger, N I; Olmstead, R et al. (2016) Preexisting mild sleep disturbance as a vulnerability factor for inflammation-induced depressed mood: a human experimental study. Transl Psychiatry 6:e750
Cho, Hyong Jin; Irwin, Michael R (2015) Is Inflammation a Link Between Self-Reported Health and Infectious Disease Risk? Psychosom Med 77:956-8