Major Depression and Molecular Senescence: The Role of Sleep

重度抑郁症和分子衰老：睡眠的作用

基本信息

批准号：
10154815
负责人：
Martica Helon Hall
金额：
$ 25.8万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10154815
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

项目摘要

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) 是导致衰弱且代价高昂的衰老疾病的一个重要危险因素。终生暴露于 MDD 会加速生物衰老，包括细胞衰老过程。我们有鉴定了一组 22 个衰老相关分泌表型 (SASP) 蛋白，这些蛋白显着在重度抑郁症缓解的老年人中升高，并可能加速这一弱势群体的生物衰老。我们还发现睡眠是加速衰老和与年龄相关的发病率的一个可改变的危险因素，死亡。我们的跨学科研究团队在睡眠和老年抑郁症的作用方面拥有专业知识衰老疾病寻求启动一项新的系统研究计划，探索睡眠作为衰老疾病的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。我们将更加关注多维睡眠健康与身体健康的相关性高于个人睡眠测量的相关性。拟议的研究旨在分析冷冻血浆样本并量化现有的、特征明确的 135 名中晚年成年人队列中的 SASP 终生有或没有复发性 MDD 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以及参与者特征。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) 至评估 SASP 与多维睡眠健康之间的关联； (3) 检查添加剂 MDD 病史和多维睡眠健康与 SASP 之间的关联。这些初步的横截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 结果，评估其对患有以下疾病的弱势成年人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以睡眠为中心的 senolytic 干预措施随机临床试验中的评估（第二次随访 R01）。这项迭代研究计划将促进我们对 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，以改善健康状况并降低患有老年疾病的弱势成年人的风险 MDD 的历史。确保未来样本的通用性对于测试和优化至关重要与睡眠相关的干预措施对老年疾病风险最大的人群的有效性。