Depression DNA Damage and Telomeres: A Chronic Stress Model of Accelerated Aging

抑郁症 DNA 损伤和端粒：加速衰老的慢性压力模型

• 批准号: 7265069
• 负责人: NAOMI M SIMON
• 金额: $ 40.98万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7265069
• 关键词: 8-hydroxy-2' -deoxyguanosine; Acceleration; Accounting; Acute; Age; Aging; Anger; Antidepressive Agents; Antioxidants; Anxiety; Anxiety Disorders; Behavior; Bereavement; Biological; Biology; CCL2 gene; Cardiovascular Diseases; Chronic; Chronic stress; Clinical; Comorbidity; Control Groups; DNA; DNA Damage; Data; Development; Disease; Elevation; Environmental Risk Factor; Exercise; Exposure to; Face; Failure; Family history of; Gender; Health; Immune; Individual; Inflammation; Inflammatory; Interleukin-1; Interleukin-6; Laboratory Finding; Length; Link; Major Depressive Disorder; Malignant Neoplasms; Measures; Mediation; Mediator of activation protein; Medical; Menopausal Status; Mental Depression; Modeling; Mood Disorders; Moods; Morbidity - disease rate; Organ; Overweight; Oxidative Stress; Panic Attack; Pathway interactions; Patients; Pharmaceutical Preparations; Pilot Projects; Positioning Attribute; Prevalence; Prevention; Process; Psychosocial Stress; Rate; Research Personnel; Risk; Risk Factors; Role; Serum; Severities; Site; Smoke; Smoking; Social support; Stress; Substance abuse problem; Symptoms; System; Telomere Shortening; Testing; Therapeutic Intervention; Tissues; Tobacco smoke; Translating; Trauma; Work; age effect; allostatic load; biological adaptation to stress; coping; cytokine; disorder control; hypothalamic-pituitary-adrenal axis; improved; mortality; novel; programs; prospective; psychologic; resilience; socioeconomics; stress related disorder; telomere

DESCRIPTION (provided by applicant): Major depressive disorder (MDD) is clearly associated with excess medical morbidity and mortality, including elevated rates of diseases that increase in prevalence with aging such as cardiovascular disease and possibly some cancers. This elevated risk remains even after accounting for differences in health related behaviors such as smoking and exercise, yet little is known about the biological mechanisms underlying this enhanced risk. However, substantial evidence supports abnormalities in stress related biological systems in MDD. Stress response mediators, while adaptive in the short-term, can result in chronic "wear and tear" to tissues and organs in the face of chronic stress responses. We hypothesize those chronic MDD results in abnormalities in stress response systems including a failure to halt acute inflammatory processes that ultimately accelerate aging. Consistent with this hypothesis and recent data showing telomere shortening with psychosocial stress, our two pilot studies demonstrated 1) significantly shorter telomere lengths in individuals with mood disorders, representing as much as 10 years of accelerated aging, and 2) significant elevations in inflammatory cytokines in those with MDD compared to matched controls. Building on recent advances in basic telomere biology and the elucidation of mechanisms underlying oxidative stress, our proposal offers a unique opportunity to translate findings from the laboratory to understanding the detrimental impact of MDD. The primary aim of this study is to examine the impact of chronic MDD as a stress related disorder on measures of accelerated aging. Specifically, DNA damage and telomere shortening, measures of chronic oxidative stress and increased cellular turnover, will be assessed in a clinically well-characterized group of 200 individuals with at least 5 years of MDD and compared to a non-psychiatrically ill age and gender matched control group. In addition, specific proinflammatory cytokines, a marker of organismal inflammation, will be examined as a potential mediator of the effect of MDD on telomere shortening and DNA damage. Detailed clinical and environmental factors will be assessed as potential moderators of the depression- accelerated aging effect. A subsample of 125 individuals with MDD and 125 matched controls will also be longitudinally followed and assessed for prospective change in these measures 2 years later. This study will advance our understanding of the impact of MDD on the development of telomere shortening and DNA damage, culminating in acceleration of aging. This work will elucidate a novel potential mechanistic pathway linking MDD and chronic stress to excess morbidity and mortality, and may reveal important possibilities for therapeutic intervention and prevention of stress related diseases of aging for individuals with MDD.

描述(申请人提供)：严重抑郁障碍(MDD)明显与过高的医疗发病率和死亡率有关，包括随年龄增长患病率增加的疾病，如心血管疾病和可能的某些癌症。即使考虑到吸烟和锻炼等与健康相关的行为的差异，这种增加的风险仍然存在，但人们对这种增加的风险背后的生物学机制知之甚少。然而，大量证据支持MDD应激相关生物系统的异常。应激反应介质虽然在短期内是适应性的，但在面对慢性应激反应时，可能会导致组织和器官的慢性“磨损”。我们假设这些慢性MDD会导致应激反应系统的异常，包括未能阻止最终加速衰老的急性炎症过程。与这一假设和最近的数据显示端粒缩短与心理社会压力相一致，我们的两项先导性研究表明：1)情绪障碍患者的端粒长度显著缩短，代表着长达10年的加速衰老；2)与匹配的对照组相比，MDD患者的炎性细胞因子显著升高。在基础端粒生物学的最新进展和对氧化应激潜在机制的阐明的基础上，我们的提案提供了一个独特的机会，可以将实验室的发现转化为了解MDD的有害影响。这项研究的主要目的是检查慢性MDD作为一种应激相关障碍对加速衰老指标的影响。具体地说，DNA损伤和端粒缩短是衡量慢性氧化应激和细胞周转增加的指标，将在200名患有至少5年MDD的临床特征良好的个体中进行评估，并与年龄和性别匹配的非精神疾病对照组进行比较。此外，特定的促炎细胞因子，一个有机体炎症的标志，将被视为MDD对端粒缩短和DNA损伤影响的潜在中介。详细的临床和环境因素将被评估为抑郁症加速衰老效应的潜在缓和因素。还将对125名MDD患者和125名匹配对照的亚样本进行纵向跟踪，并评估2年后这些指标的预期变化。这项研究将增进我们对MDD对端粒缩短和DNA损伤的影响的理解，最终导致衰老的加速。这项工作将阐明MDD和慢性应激与过度发病率和死亡率之间的潜在机制，并可能为MDD患者的应激相关衰老疾病的治疗干预和预防提供重要的可能性。