Cell Aging in Major Depression

重度抑郁症中的细胞老化

• 批准号: 8427369
• 负责人: Elissa S. Epel
• 金额: $ 50.97万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8427369
• 关键词: Accounting; Affect; Aging; Aging-Related Process; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Ascorbic Acid; Biochemical; Biological; Biological Aging; Biological Assay; Biological Models; Biology; Brain; Cardiovascular Diseases; Cell Aging; Cells; Cellular biology; Comorbidity; DNA; Data; Dementia; Depressed mood; Development; Disease; F2-Isoprostanes; Functional disorder; Goals; Hippocampus (Brain); Immune system; Impairment; Individual; Inflammatory; Interleukin-10; Interleukin-6; Length; Magnetic Resonance Imaging; Major Depressive Disorder; Mediating; Mediator of activation protein; Medical; Mental Depression; Modeling; Molecular; Morbidity - disease rate; Neuraxis; Occupational; Outcome Measure; Oxidative Stress; Peripheral; Peripheral Blood Mononuclear Cell; Phenotype; Population; Premature aging syndrome; Prevention; Recruitment Activity; Resolution; Risk; Sample Size; Sampling; Serum; Stream; Stress; System; Telomere Shortening; Text; Urine; age related; cell age; cytokine; dentate gyrus; disability; immune function; insight; mortality; neurogenesis; neuroimaging; peripheral blood; psychologic; public health relevance; social; telomere; theories; ultra high resolution

DESCRIPTION (provided by applicant): Major depression, a disease affecting up to 16% of the population at some point in their lives, has been likened to a state of "accelerated aging," with an increased risk of acquiring certain diseases of aging, such as immune function impairment, cardiovascular disease and dementia. Depression may also be associated with accelerated aging at the level of the individual cell. The biological mechanisms underlying such cellular vulnerability and increased risk of co-morbid diseases remain unknown. We will explore a model in which depression-associated oxidative stress and inflammatory stress are related to accelerated aging in two model systems, one peripheral and one central. Specifically, we will assess whether: (1) telomeres are shortened in the DNA of peripheral blood mononuclear cells (PBMC's) of depressed individuals; (2) hippocampal (total and subfield) volumes are decreased in depressed individuals; and (3) accelerated aging in both of these systems is mediated by increased oxidative stress and pro-inflammatory cytokine activity. Our preliminary data suggest that PBMC telomeres are shortened in depressed individuals, especially those with longer durations of untreated depression, representing between 8-9 years of accelerated biological aging. In non-depressed populations, short PBMC telomeres have been related to significant medical morbidity and early mortality, raising the possibility that our observed changes in PBMD telomere length in depression contributes to medical morbidity in these individuals. Our preliminary neuroimaging data, while limited by small sample sizes, suggest diminished volume of the hippocampus, and of the CA3/dentae gyrus subfield, in particular, the region involved in neurogenesis. Importantly, our preliminary data also suggest that PBMC telomere length and hippocampal volume are both inversely correlated with oxidative and inflammatory stress. This raises the possibility of conjoint peripheral-central accelerated aging processes in depression, with similar biochemical mediators underlying both. Our primary aims are to determine whether PBMC telomere shortening and hippocampal volume loss occur in major depression, whether oxidative and inflammatory stress are increased in major depression, and whether these putative biochemical mediators of accelerated aging are correlated with our outcome measures. To accomplish this, 82 un-medicated depressed subjects and 82 matched controls will have PBMC's assayed for telomere length, and a subset of 55 un-medicated depressed subjects and 55 matched controls will additionally undergo ultra-high resolution brain MRI scans to assess hippocampal and hippocampal subfield volumes. All subjects will have serum and urine assayed for putative biochemical mediators. Path analysis will determine whether these biochemical levels mediate the relationship between depression and PBMC telomere length and hippocampal volume. Discovering fundamental changes in telomere cell biology and in hippocampal aging will advance our understanding of the pathophysiology of major depression and of its medical co-morbidities, and will present new targets for prevention and treatment.

描述（由申请人提供）：重度抑郁症是一种影响人口的16％的疾病，在他们生活中的某个时刻被比作了一种“加速衰老”的状态，增加了某些衰老疾病的风险，例如免疫功能障碍，心血管疾病和痴呆症。抑郁症也可能与单个细胞水平的加速衰老有关。这种细胞脆弱性和合并症风险增加的生物学机制尚不清楚。我们将探讨一个模型，其中与抑郁症相关的氧化应激和炎症应激与两个模型系统中的加速衰老有关，一个外围和一个中心。具体而言，我们将评估：（1）在抑郁症患者的外周血单核细胞（PBMC）的DNA中是否缩短了端粒； （2）抑郁个体的海马（总和子场）体积减少； （3）这两个系统中的加速衰老都是由氧化应激和促炎性细胞因子活性增加的。 我们的初步数据表明，在抑郁症的个体中，尤其是那些未经治疗的抑郁症持续时间较长的人，PBMC端粒被缩短，代表了8 - 9年的加速生物衰老。在不抑郁的人群中，较短的PBMC端粒与明显的医疗发病率和早期死亡率有关，从而增加了我们观察到的抑郁症中PBMD端粒长度变化的可能性有助于这些人的医疗发病率。我们的初步神经影像学数据虽然受小样本量的限制，但表明海马体的体积减少，尤其是CA3/Dentae Gyrus子场，尤其是参与神经发生的区域。重要的是，我们的初步数据还表明，PBMC端粒长度和海马体积都与氧化和炎症应激成反比。这增加了抑郁症的联合中心加速衰老过程的可能性，而这两者都具有相似的生化介质。 我们的主要目的是确定在严重抑郁症中PBMC端粒缩短和海马体积损失是否发生在重度抑郁症中是否增加，以及这些假定的加速衰​​老的生物化学介质是否与我们的结果测量相关。为此，82个未经物质的抑郁症受试者和82个匹配的对照将对PBMC进行端粒长度的测定，以及55个未介导的抑郁症受试者的子集和55个匹配的对照组将进行超高分辨率的大脑MRI扫描，以评估Hippocampal和Hippocampampal subippocampal subippocampal volumes volumes。所有受试者均将用于假定的生化介质的血清和尿液分析。路径分析将确定这些生化水平是否介导抑郁症与PBMC端粒长度和海马体积之间的关系。发现端粒细胞生物学和海马衰老的根本变化将使我们对大抑郁症及其医学合并症的病理生理学的理解，并将为预防和治疗提供新的目标。