A Randomized Trial for Sleep Disturbances to Reverse Cellular Aging

 描述（由申请人提供）：需要进行研究，以弥合从行为因素到分子应激的连续统一体，确定细胞衰老在与年龄相关的炎症上升中的作用，并确定可能改变衰老过程并最终改善健康寿命的干预策略。目前的提案旨在通过针对睡眠来解决这一需求，睡眠是一种与衰老和年龄相关疾病有关的可改变的行为。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慢性疾病的风险。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。该项目将利用正在进行的随机临床试验（RCT; R 01 AG 026364;欧文）正在测试使用睡眠质量认知行为疗法（CBT-SQ）与睡眠研讨会（SS）治疗睡眠障碍是否能控制、改善睡眠并降低有睡眠投诉的非抑郁老年人的抑郁风险（匹兹堡睡眠质量指数，PSQI >5; n=305），在基线、12个月、18个月、24个月、36个月进行评估。在这个项目中，我们的目标是：1）评估CBT-SQ与SS对3年内细胞衰老标志物的影响。假设1：相对于SS，CBT-SQ治疗睡眠障碍将改善线粒体功能，增加端粒酶活性，延长PBMC端粒，并在3年内减少关键衰老相关基因的表达。2)评估6个月时睡眠障碍缓解（PSQI <5）与未缓解的睡眠障碍对3年随访期间细胞衰老标志物的影响。假设二：相对于缓解者，在6个月时患有持续睡眠障碍（PSQI Global >5）的那些人将显示出更差的线粒体功能、更低的端粒酶、更短的PBMC端粒以及超过3年的关键衰老相关基因的更高表达。探索性目的：为了解决当前知识中的关键差距，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DNA表观遗传甲基化模式，以提供对睡眠障碍对细胞生物学作用的新认识。此外，我们将使用从亲本R 01收集的现有炎症数据来检查细胞衰老和炎症之间可能的双向关系（即，发炎）。影响声明：拟议的项目解决了生物行为睡眠研究领域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会逆转细胞衰老过程的研究，使用该过程的许多创新分子生物标志物超过3年，并利用一个强大的和证明的RCT来治疗睡眠障碍。这项工作有可能暗示晚年睡眠障碍与生物衰老的进展有关，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.