Major Depression and Molecular Senescence: The Role of Sleep

严重抑郁障碍(MDD)是导致衰弱和代价高昂的老年病的重要风险因素。 终生接触MDD会加速生物衰老，包括细胞衰老过程。我们有 确定了22种衰老相关分泌表型(SASP)蛋白的簇，这些蛋白与 在患有缓解性MDD的老年人中升高，并可能加速这一脆弱人群的生物衰老。 我们还发现睡眠是加速衰老和与年龄相关的发病率的可改变的风险因素， 死亡率。我们的跨学科研究团队在睡眠和老年性抑郁症的作用方面具有专业知识 老年病寻求启动一项新的系统性研究计划，将睡眠作为研究的目标 减少抑郁症暴露对生物衰老加速及其下游后果的影响 为健康和功能干杯。我们将专注于多维睡眠健康，这是一个更加强烈的问题 与身体健康相关的指标比个人衡量睡眠的指标要高。这项拟议的研究试图对冰冻的 在135名中老年成年人中采集血浆样本并量化SASP 有和没有复发性MDD终生病史。血液样本是同时采集的 精神病学数据，多维睡眠健康的多模式指数，以及参与者的特征。 与R21机制的探索性一致，这项研究的总体目标是探索 MDD暴露、多维睡眠健康和SASP之间关联的大小和方向。 我们有三个具体目标：(1)评估SASP与MDD病史之间的关联；(2)评估SASP与MDD病史之间的关联 评估SASP和多维睡眠健康之间的关联；以及(3)检查添加剂 MDD病史和多维度睡眠健康状况与SASP的关系。这些初步的 横断面数据将为规划的纵向设计提供信息，并支持其基本原理 后续研究。在第一个后续R01中，我们将实验性地操纵多维睡眠健康 根据R21的结果，并评估其对患有老年痴呆症的易患成年人加速生物衰老的因果影响 抑郁症病史。这些数据将被用来开发一种以睡眠为重点的感觉性干预措施 在随机临床试验(第二次随访R01)中进行评估。这一研究的迭代计划将既 促进我们对MDD增加发病率和死亡率的机制的科学理解 并为临床实践提供信息，以改善健康并降低患有老年疾病的脆弱成年人的风险 MDD的历史。确保在未来样本中的通用性将是测试和优化 与睡眠相关的干预措施在老年病高危人群中的有效性。

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.