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）是一个重要的危险因素，使人衰弱和昂贵的老年疾病。 终生暴露于MDD会加速生物老化，包括细胞衰老过程。我们有 鉴定了一组22种衰老相关分泌表型（SASP）蛋白， 在缓解的MDD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年龄相关疾病的一个可改变的风险因素， mortality.我们的跨学科研究团队在睡眠和老年抑郁症的作用方面具有专业知识， 衰老疾病寻求启动一项新的系统研究计划，探讨睡眠作为衰老的目标 减少抑郁暴露对加速生物衰老及其下游后果的影响 健康和功能。我们将重点关注多维睡眠健康， 与身体健康的关系要比单独的睡眠测量更密切。这项拟议中的研究旨在分析冷冻的 血浆样本和定量SASP在一个现有的，良好的特点队列的135个中年至晚年的成年人 有无复发性抑郁症的终生病史。同时采集血样， 精神病学数据、多维睡眠健康的多模态指数和参与者特征。 与R21机制的探索性质一致，本研究的总体目标是探索 MDD暴露、多维度睡眠健康和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病史之间的关系;（2） 评估SASP和多维睡眠健康之间的关联;（3）检查添加剂 抑郁症病史和多维度睡眠健康与SASP的关系。这些初步 横截面数据将为计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R 01中，我们将实验性地操纵多维睡眠健康 根据R21结果，评估其对具有以下特征的脆弱成人的加速生物衰老的因果影响： 抑郁症史。这些数据将反过来用于开发一种以睡眠为重点的衰老干预措施， 在随机临床试验中进行评价（第二次随访R 01）。这一反复的研究计划将既 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，以改善健康状况，降低患有老年疾病的脆弱成年人的风险。 MDD的历史确保未来样本的普遍性对于测试和优化 在老年疾病风险最高的人群中进行睡眠相关干预的有效性。