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）明显与过高的医疗发病率和死亡率相关，包括心血管疾病和某些癌症等随着年龄增长而增加的疾病发病率升高。即使在考虑了吸烟和锻炼等健康相关行为的差异后，这种增加的风险仍然存在，但人们对这种风险增加的生物学机制知之甚少。然而，大量证据支持重度抑郁症中与压力相关的生物系统异常。应激反应介质虽然在短期内具有适应性，但在面对慢性应激反应时，可能导致组织和器官的慢性“磨损”。我们假设慢性重度抑郁症会导致应激反应系统的异常，包括无法阻止最终加速衰老的急性炎症过程。与这一假设和最近显示端粒缩短与社会心理压力有关的数据相一致，我们的两项初步研究表明：1)情绪障碍患者端粒长度显著缩短，代表了长达10年的加速衰老；2)与对照组相比，重度抑郁症患者的炎症细胞因子显著升高。基于基础端粒生物学的最新进展和氧化应激机制的阐明，我们的建议提供了一个独特的机会，将实验室的发现转化为理解MDD的有害影响。本研究的主要目的是研究慢性重度抑郁症作为一种压力相关疾病对加速衰老的影响。具体来说，DNA损伤和端粒缩短，慢性氧化应激和细胞更新增加的测量，将在临床特征明确的200名至少5年重度抑郁症患者中进行评估，并与年龄和性别匹配的非精神疾病对照组进行比较。此外，特异性促炎细胞因子，机体炎症的标志物，将被检查作为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潜在的调节抑郁-加速衰老效应。对125名重度抑郁症患者和125名匹配对照的子样本进行纵向随访，并评估2年后这些指标的预期变化。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，最终加速衰老。这项工作将阐明将重度抑郁症和慢性应激与过度发病率和死亡率联系起来的一种新的潜在机制途径，并可能为重度抑郁症患者的治疗干预和预防应激相关的衰老疾病提供重要的可能性。

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