Major Depression and Molecular Senescence: The Role of Sleep

重度抑郁症和分子衰老：睡眠的作用

• 批准号: 10493092
• 负责人: MERYL A BUTTERS
• 金额: $ 10.98万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10493092
• 关键词: Acute; Adult; Age; Aging; Attenuated; Biological; Biological Aging; Biological Assay; Biological Process; Blood specimen; Cell Aging; Cell physiology; Characteristics; Clinical; Complex; Cost of Illness; Critical Pathways; Data; Depressed mood; Development; Dimensions; Disease; Effectiveness; Elderly; Ensure; Evaluation; Exploratory/Developmental Grant; Exposure to; Follow-Up Studies; Freezing; Future; Health; Individual; Intervention; Link; Major Depressive Disorder; Measures; Medical; Mental Depression; Molecular; Morbidity - disease rate; Nature; Participant; Pathway interactions; Phenotype; Plasma; Population; Prevalence; Process; Proteins; Randomized Clinical Trials; Recording of previous events; Recurrence; Reporting; Research; Risk Factors; Role; Sampling; Seeds; Sleep; Sleep disturbances; Sleeplessness; Testing; Vulnerable Populations; age related; alertness; base; clinical practice; cohort; comorbidity; depressive symptoms; design; disability; disorder risk; follow-up; geriatric depression; improved; indexing; modifiable risk; mortality; multimodality; physical conditioning; precision medicine; programs; satisfaction; senescence; sex; sleep health; sleep quality

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.

重度抑郁症（MDD）是衰老和昂贵的衰老疾病的重要危险因素。 终生暴露于MDD会加速生物衰老，包括细胞衰老的过程。我们有 鉴定出22个与衰老相关的分泌表型（SASP）蛋白的簇显着 在患有MDD的老年人中升高，可能会加速这一脆弱人群的生物衰老。 我们还确定睡眠是加速衰老和与年龄相关的发病率的可修改风险因素 死亡。我们的跨学科研究团队在睡眠和老年抑郁症的角色方面具有专业知识 衰老疾病试图启动一项新的系统研究计划，以探测睡眠作为目标 减少抑郁症暴露对加速生物衰老及其下游后果的影响 健康和功能。我们将专注于多维睡眠健康 与身体健康相关，而不是单个睡眠措施。拟议的研究旨在测定冻结的 血浆样品并量化现有的135个中后期成年人的现有的，良好的特征良好的队列中的SASP 有和没有一生的复发性MDD历史。同时收集血液样本 精神病数据，多维睡眠健康的多模式指数和参与者特征。 与R21机制的探索性质一致，研究的总体目的是探索 MDD暴露，多维睡眠健康和SASP之间关联的大小和方向。 我们有三个具体的目标：（1）评估MDD的SASP和历史之间的关联； （2）至 评估SASP与多维睡眠健康之间的关联； （3）检查添加剂 MDD史与SASP的多维睡眠健康之间的关联。这些初步 横截面数据将为计划的纵向提供信息，并支持基本原理 后续研究。在第一次后续R01中，我们将通过实验操纵多维睡眠健康 根据R21的结果并评估其对脆弱成年人加速生物衰老的因果影响 抑郁史。这些数据又将使用以睡眠为中心 在一项随机临床试验中评估（第二个随访R01）。这个迭代的研究计划都将 促进我们对MDD提高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脆弱成年人的衰老疾病风险 MDD的历史。确保未来样本中的普遍性对于测试和优化至关重要 与睡眠有关的人群中与衰老疾病风险最大的人群干预措施的有效性。