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）：重度抑郁症是一种在一生中的某个阶段影响多达 16% 人口的疾病，被比作“加速衰老”状态，患某些衰老疾病的风险增加，例如免疫功能受损、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。这种细胞脆弱性和共病风险增加的生物学机制仍然未知。我们将探索一种模型，其中抑郁相关的氧化应激和炎症应激与两个模型系统（一个外周系统和一个中枢系统）的加速衰老有关。具体来说，我们将评估：(1) 抑郁症患者的外周血单核细胞 (PBMC) 的 DNA 中端粒是否缩短； (2) 抑郁症患者的海马体（总海马区和亚区）体积减少； (3)这两个系统中的加速衰老是由氧化应激和促炎细胞因子活性增加介导的。 我们的初步数据表明，抑郁症个体的 PBMC 端粒缩短，尤其是那些抑郁症持续时间较长且未经治疗的个体，代表着 8-9 年的加速生物衰老。在非抑郁人群中，短 PBMC 端粒与显着的医疗发病率和早期死亡率相关，这增加了我们观察到的抑郁症患者 PBMD 端粒长度的变化可能导致这些个体的医疗发病率。我们的初步神经影像数据虽然受到小样本量的限制，但表明海马体和 CA3/齿状回亚区的体积减小，特别是涉及神经发生的区域。重要的是，我们的初步数据还表明，PBMC 端粒长度和海马体积均与氧化应激和炎症应激呈负相关。这提出了抑郁症中联合外周-中枢加速衰老过程的可能性，两者背后有类似的生化介质。 我们的主要目的是确定重度抑郁症中是否发生 PBMC 端粒缩短和海马体积损失，重度抑郁症中氧化应激和炎症应激是否增加，以及这些假定的加速衰​​老生化介质是否与我们的结果测量相关。为了实现这一目标，82 名未接受药物治疗的抑郁症受试者和 82 名匹配的对照者将进行 PBMC 端粒长度检测，55 名未接受药物治疗的抑郁症受试者和 55 名匹配的对照者中的一部分将另外接受超高分辨率脑部 MRI 扫描，以评估海马和海马亚区体积。所有受试者都将检测血清和尿液中推定的生化介质。通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增进我们对重度抑郁症及其医学并发症的病理生理学的理解，并将提出预防和治疗的新目标。