Major Depression and Molecular Senescence: The Role of Sleep

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Major depressive disorder (MDD) is a significant risk factor for debilitating and costly diseases of aging. Lifetime exposure to MDD accelerates biological aging, including processes of cellular senescence. We have identified a cluster of 22 senescence-associated secretory phenotype (SASP) proteins that are significantly elevated in older adults with remitted MDD and may accelerate biological aging in this vulnerable population. We have also identified sleep as a modifiable risk factor for accelerated aging and age-related morbidity and mortality. Our transdisciplinary research team with expertise in the roles of sleep and geriatric depression in diseases of aging seeks to launch a new systematic program of research that probes sleep as a target for reducing the impact of depression exposure on accelerated biological aging and its downstream consequences to health and functioning. We will focus on multidimensional sleep health which has been more strongly associated with physical health than individual measures of sleep. The proposed study seeks to assay frozen plasma samples and quantify the SASP in an existing, well-characterized cohort of 135 mid- to late-life adults with and without a lifetime history of recurrent MDD. Blood samples were collected concurrently with psychiatric data, multimodal indices of multidimensional sleep health, and participant characteristics. Consistent with the exploratory nature of the R21 mechanism, the overall aim of the study is to explore the magnitude and direction of associations among MDD exposure, multidimensional sleep health, and the SASP. We have three specific aims: (1) To evaluate associations between the SASP and history of MDD; (2) To evaluate associations between the SASP and multidimensional sleep health; and (3) To examine additive associations among history of MDD and multidimensional sleep health with the SASP. These preliminary cross-sectional data will inform the design of, and support the rationale for, planned longitudinal follow-up studies. In the first follow-up R01, we will experimentally manipulate multidimensional sleep health per R21 results and evaluate their causal impact on accelerated biological aging in vulnerable adults with a history of depression. These data will be used, in turn, to develop a sleep-focused senolytic intervention for evaluation in a randomized clinical trial (second follow-up R01). This iterative program of research will both advance our scientific understanding of the mechanisms through which MDD increases morbidity and mortality and inform clinical practice to improve health and reduce risk for diseases of aging in vulnerable adults with a history of MDD. Ensuring generalizability in future samples will be critical to testing and optimizing the effectiveness of sleep-related interventions in populations at greatest risk for diseases of aging.