A Randomized Trial for Sleep Disturbances to Reverse Cellular Aging

 描述(申请人提供)：需要研究来弥合从行为因素到分子压力的连续体，确定细胞老化在与年龄相关的炎症增加中的作用，并确定可能改变衰老过程并最终改善健康生活年数的干预策略。目前的提案试图通过针对睡眠来满足这一需求，睡眠是一种可改变的行为，已被认为与衰老和年龄相关疾病有关。睡眠障碍可能通过加速衰老和与年龄相关的炎症增加而增加患慢性病的风险。到目前为止，还没有研究证明睡眠障碍在这些途径中的作用，也没有测试使用高效行为策略缓解睡眠障碍是否会逆转细胞衰老过程。这个项目将利用正在进行的随机临床试验(RCT；R01 AG026364；Irwin)，该试验正在测试在3年的跟踪调查中，是否使用睡眠质量认知行为疗法(CBT-SQ)与睡眠研讨会(SS)治疗睡眠障碍，控制、改善睡眠并降低患有抑郁症的风险(匹兹堡睡眠质量指数，PSQI&GT；5；n=305)，并在基线、12个月、18个月、24个月、36个月进行评估。在本项目中，我们将致力于：1)评估CBT-SQ与SS在3年内对细胞衰老标志物的影响。假设1：相对于SS，CBT-SQ治疗睡眠障碍将在3年内改善线粒体功能，增加端粒酶活性，延长PBMC端粒，并减少关键衰老相关基因的表达。2)评价6个月后睡眠障碍缓解(PSQI&lt；5)与未缓解睡眠障碍对细胞老化指标的影响。假设2：相对于有持续睡眠障碍(PSQI Global&gt；5)的患者，6个月大的患者在3年内线粒体功能较差，端粒酶较低，PBMC端粒较短，关键衰老相关基因的表达较高。探索性目标：为了解决当前知识中的关键空白，我们将应用发现科学方法，使用先进的生物信息学方法来解释全基因组基因表达阵列和与年龄相关的表观遗传DNA甲基化模式，以提供对睡眠障碍对细胞生物学作用的新理解。此外，我们将使用从亲本R01收集的现有炎症数据来检查细胞老化和炎症(即炎症)之间可能的双向关系。影响陈述：拟议的项目解决了生物行为睡眠研究领域中的一个非常重要的问题，因为它将是第一个研究睡眠障碍的治疗是否逆转细胞衰老过程的研究，使用这一过程的许多创新分子生物标记物，并利用动力良好和经过验证的随机对照试验来治疗睡眠障碍。这项工作有可能将晚年睡眠障碍与生物衰老的进程联系起来，并证明治疗老年人睡眠障碍的干预措施可能会减缓甚至逆转细胞衰老。

 DESCRIPTION (provided by applicant): Research is needed to bridge the continuum from behavioral factors to molecular stress, define the role of cellular aging in age related rises in inflammation, and identify interventional strategies that may alter the course of aging and ultimately improve the number of healthy years of living. The current proposal seeks to address this need by targeting sleep, a modifiable behavior that has been linked to aging and age related disease. Sleep disturbances elevate risk for chronic disease, possibly by accelerating aging and age related rises in inflammation. No research to date has demonstrated a role of sleep disturbances in these pathways nor tested whether remission of sleep disturbances using highly efficacious behavioral strategies reverses the cellular aging processes. This project will leverage an ongoing randomized clinical trial (RCT; R01 AG026364; Irwin) that is testing whether treatment of sleep disturbance using cognitive behavioral therapy for sleep quality (CBT-SQ) vs. sleep seminar (SS), controls, improves sleep and reduces the risk for depression in non-depressed older adults with sleep complaints (Pittsburgh Sleep Quality Index, PSQI >5; n=305) over a 3-year follow-up with assessments at baseline, 12 months, 18 months, 24 months, 36 months. In this project, we will aim to: 1) evaluate the effects of CBT-SQ vs. SS on markers of cellular aging over 3-years. Hypothesis 1: Relative to SS, CBT-SQ for sleep disturbances will improve mitochondrial function, increase telomerase activity, lengthen PBMC telomeres, and reduce expression of key aging related genes over 3-years. 2) Evaluate the effects of sleep disturbance remission (PSQI <5) at 6 months vs. unremitted sleep disturbance on markers of cellular aging over 3 years follow-up. Hypothesis 2: Relative to remitters, those with unremitting sleep disturbances (PSQI Global >5) at 6 months will show poorer mitochondrial function, lower telomerase, shorter PBMC telomeres, and greater expression of key aging related genes over 3-years. Exploratory Aim: To address critical gaps in current knowledge, we will apply discovery science approaches using advanced bioinformatics methods to interpret whole genome gene expression arrays and age related epigenetic methylation patterns to DNA to provide novel understanding in the role of sleep disturbances to cellular biology. In addition, we will use existing inflammatory data collected from the parent R01 to examine a possible bi- directional relationship between cellular aging and inflammation (i.e., inflammaging). Impact Statement: The proposed project addresses a very significant issue in the field of biobehavioral sleep research as it will be the first study to examine whether treatment of sleep disturbances reverses processes of cellular aging, using numerous innovative molecular biomarkers of this process over 3 years, and leveraging a well powered and demonstrated RCT to treat sleep disturbances. This work has the potential to implicate late life sleep disturbances in the progression of biological aging, and to demonstrate that interventions to treat sleep disturbances in older adults may slow or even reversing cellular aging.