Accelerated Inflammaging in Schizophrenia

项目总结/摘要 精神分裂症（SZ）是最致残的精神疾病之一，也与医疗费用的增加有关。 合并症和20年的寿命短于一般人群，这一切都表明，深圳是 以加速老化为特征。为了验证这一假设，本申请将我们的 SZ的R 01代表了评估SZ患者10年衰老轨迹的独特机会， 健康的比较受试者（HC），并将重点扩大到检查严重的真实的世界后果 （身体合并症和死亡率）、潜在可改变的风险因素以及炎症和细胞标志物 衰老的迹象根据我们最初的建议，采用多队列纵向设计（MCLD），我们开发了 140例SZ和120例HC受试者的性别和年龄分层队列，基线时年龄为26-65岁。这些 每年对参与者进行临床评估，并使用一组选定的标志物代表 在交替的年份中生物老化。生物标志物包括炎症过程的系统测量 （高敏C反应蛋白或hs-CRP，沿着另一种细胞因子和两种趋化因子），代谢 调节异常（胰岛素抵抗稳态模型评估; HOMA-IR）、氧化应激（F2-IR） 异前列腺素）和细胞老化（端粒长度）。我们目前处于5年项目的第49个月，但 目前正在提议在其完成之前进行这种竞争性更新，以避免资金缺口，并确保保留 这一宝贵的、特征鲜明的现有群体。我们的留存率一直很高（深圳每年95%）。 我们有初步证据与SZ的加速生物老化一致;然而， 有必要扩大研究，增加新的目标和创新措施， 加速的后果和风险因素，并检查基因表达的机制作用， 与炎症相关的信号通路。建议的更新是由我们的 最初的发现，以及关于炎症和其他生物学和细胞机制的不断发展的文献， 衰老在接下来的五年里，我们将继续评估目前生物标志物的轨迹， 增加了炎症信号传导、炎症和细胞衰老转录组学谱的新测量方法 （“发炎”）。我们将加强我们的表征物理comormands和行为，包括使用 身体活动和日常功能的移动的评估，并增加生物标志物的频率 每18个月评估一次。该项目与NIMH战略目标#2有关： 疾病轨迹，以确定何时，何地以及如何干预。展示存在感， 表征SZ加速生物老化的模式将大大促进对 现实世界的后果，风险因素和潜在机制，这些因素将共同为新的方法提供信息， 预测、跟踪和治疗严重的医学共病，降低SZ的死亡率。最终 我们的目标是改善整体健康状况，延长SZ患者的寿命。

Project Summary/Abstract Schizophrenia (SZ), one of the most disabling mental illnesses, is also associated with increased medical comorbidity and a 20-year shorter life-span than the general population, which together suggest that SZ is characterized by accelerated aging. To examine that hypothesis, this application for a 5-year renewal of our R01 in SZ represents a unique opportunity to evaluate 10-year trajectories of aging in persons with SZ and healthy comparison subjects (HCs), and to expand the focus to examine serious real world consequences (physical comorbidity and mortality), potentially modifiable risk factors, and inflammatory and cellular markers of aging. Per our original proposal, employing a Multi-Cohort Longitudinal Design (MCLD), we have developed a sex- and age-stratified cohort of 140 subjects with SZ and 120 HCs, aged 26-65 years at baseline. These participants are evaluated clinically every year, and with a panel of selected markers representative of biological aging in alternate years. The biomarkers include systemic measures of inflammatory processes (high-sensitivity C-reactive protein or hs-CRP, along with another cytokine and two chemokines), metabolic dysregulation (Homeostatic Model Assessment of Insulin Resistance; HOMA-IR), oxidative stress (F2- isoprostanes), and cellular aging (telomere length). We are currently in the 49th month of the 5-year project, but are proposing this competitive renewal prior to its completion, to avoid a gap in funding and ensure retention of this invaluable, well-characterized existing cohort. Our retention rate has been excellent (95% annually for SZ). We have preliminary evidence consistent with accelerated biological aging in SZ; however, a 10-year expanded study with additional novel aims and innovative measures is necessary to characterize consequences and risk factors of acceleration, and examine the mechanistic role of gene expression and signaling pathways related to inflammation. The proposed renewal has been designed and informed by our initial findings, and by the evolving literature on inflammation and other biological and cellular mechanisms of aging. During the next five years, we will continue to evaluate trajectories of the current biomarkers, while adding novel measures of inflammatory signaling, and inflammation and cellular aging transcriptomic profiles (“inflammaging”). We will enhance our characterization of physical comorbidity and behaviors, including using mobile assessment of physical activity and everyday functioning, and increase the frequency of biomarker assessments to every 18 months. This project is related to the NIMH Strategic Objective # 2: charting mental illness trajectories to determine when, where, and how to intervene. Demonstrating the presence and characterizing the patterns of accelerated biological aging in SZ will significantly advance understanding of the real-world consequences, risk factors, and underlying mechanisms, which together will inform new ways of predicting, tracking, and treating the serious medical co-morbidities and reducing mortality in SZ. The ultimate goal is to improve the overall health and increase the life-span of people living with SZ.