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: 8044680
• 负责人: NAOMI M SIMON
• 金额: $ 38.68万
• 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/8044680
• 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; Environmental Risk Factor; Exercise; Exposure to; 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; Morbidity - disease rate; Organ; Overweight; Oxidative Stress; Panic Attack; Pathway interactions; Patients; Pharmaceutical Preparations; Pilot Projects; Prevalence; Prevention; Process; Psychosocial Stress; Research Personnel; Risk; Risk Factors; Role; Serum; Severities; Site; Smoking; Social support; Socioeconomic Status; 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; biological systems; coping; cytokine; disorder control; hypothalamic-pituitary-adrenal axis; improved; mortality; novel; programs; prospective; psychologic; resilience; 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（由申请人提供）：重度抑郁症（MDD）显然与医疗发病率过多和死亡率有关，包括升高的疾病率升高，随着衰老（例如心血管疾病）以及可能是某些癌症的患病率增加。即使考虑到与健康相关行为（例如吸烟和运动）的差异，这种升高的风险仍然存在，但对这种增强风险的生物学机制知之甚少。但是，大量证据支持MDD中与压力相关的生物系统的异常。压力反应介质虽然在短期内进行适应性，但在面对慢性应激反应的情况下可能会导致组织和器官的慢性“磨损”。我们假设这些慢性MDD导致压力反应系统中的异常，包括无法停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一致，显示端粒缩短了与社会心理压力的缩短，我们的两项试点研究表明1）与匹配的对照组相比，患有情绪障碍的个体的端粒长度明显短，代表了多达10年的加速衰老，而2）炎症细胞因子的显着升高。在基本的基本端粒生物学的最新进展以及阐明氧化应激基础机制的最新进展的基础上，我们的建议提供了一个独特的机会，可以转化实验室的发现，以了解MDD的有害影响。这项研究的主要目的是检查慢性MDD作为应激障碍对加速衰老测量的影响。具体而言，将在临床上良好的200个患者的临床表征良好的组中评估DNA损伤和端粒缩短，慢性氧化应激的度量和增加的细胞周转率，并与至少5年的MDD相比，并将其与非精神病患者的年龄和性别匹配的对照组进行了比较。此外，将研究特定的促炎细胞因子是生物体炎症的标志物，作为MDD对端粒缩短和DNA损伤作用的潜在介体。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调节剂。 125个具有MDD和125个匹配对照的人的子样本也将纵向遵循并评估2年后的这些措施中的前瞻性变化。这项研究将促进我们对MDD对端粒缩短和DNA损伤发展的影响的理解，并在衰老加速时达到高潮。这项工作将阐明将MDD和慢性应激与过量发病率和死亡率联系起来的新型潜在机械途径，并可能揭示了治疗干预和预防MDD患者衰老的压力相关疾病的重要可能性。

项目成果

Telomere length and telomerase in a well-characterized sample of individuals with major depressive disorder compared to controls.

与对照组相比，重度抑郁症个体的明确特征样本中的端粒长度和端粒酶。

• DOI: 10.1016/j.psyneuen.2015.04.004
• 发表时间: 2015
• 期刊: Psychoneuroendocrinology
• 影响因子: 3.7
• 作者: Simon,NaomiM;Walton,ZandraE;Bui,Eric;Prescott,Jennifer;Hoge,Elizabeth;Keshaviah,Aparna;Schwarz,Noah;Dryman,Taylor;Ojserkis,RebeccaA;Kovachy,Benjamin;Mischoulon,David;Worthington,John;DeVivo,Immaculata;Fava,Maurizio;Wong,Kw
• 通讯作者: Wong,Kw

Prospective association between major depressive disorder and leukocyte telomere length over two years.

两年内重度抑郁症与白细胞端粒长度之间的前瞻性关联。

• DOI: 10.1016/j.psyneuen.2018.02.015
• 发表时间: 2018
• 期刊: Psychoneuroendocrinology
• 影响因子: 3.7
• 作者: Vance,MaryC;Bui,Eric;Hoeppner,SusanneS;Kovachy,Benjamin;Prescott,Jennifer;Mischoulon,David;Walton,ZandraE;Dong,Melissa;Nadal,MireyaF;Worthington,JohnJ;Hoge,ElizabethA;Cassano,Paolo;Orr,EstherH;Fava,Maurizio;deVivo,Imma
• 通讯作者: deVivo,Imma