Accelerated Inflammaging in Schizophrenia

项目摘要/摘要 精神分裂症(SZ)是致残程度最高的精神疾病之一，也与医疗费用的增加有关 合并症和比普通人群短20岁的寿命，这些共同表明SZ是 以加速衰老为特征。为了检验这一假设，这份申请将我们的 SZ的R01是评估SZ和SZ患者10年衰老轨迹的独特机会 健康比较对象(HCS)，并将重点扩大到审查现实世界的严重后果 (身体共病和死亡率)，潜在的可改变的危险因素，以及炎症和细胞标志物 衰老的问题。根据我们最初的建议，采用多队列纵向设计(MCLD)，我们开发了 按性别和年龄分层的队列包括140名SZ患者和120名HCS患者，基线年龄为26-65岁。这些 参与者每年都要接受临床评估，并由一组代表 交替年份的生物老化。这些生物标记物包括炎症过程的系统性指标。 (高敏C反应蛋白或hs-CRP，以及另一种细胞因子和两种趋化因子)，代谢 失调(胰岛素抵抗的稳态模型评估；HOMA-IR)，氧化应激(F2- 异前列腺素)和细胞衰老(端粒长度)。我们目前正处于5年项目的第49个月，但 在完成之前提出这项竞争性续签，以避免资金缺口并确保保留 这个无价的，特征良好的现有队列。我们的留存率一直很高(深圳每年95%)。 我们有初步证据表明深圳生物老龄化加速；然而，10年 有必要扩大研究，增加新的目标和创新的措施，以确定 加速的后果和风险因素，并检查基因表达和 与炎症相关的信号通路。建议的续期是由我们的 初步发现，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。在未来五年，我们将继续评估当前生物标志物的轨迹，同时 增加炎症信号、炎症和细胞老化转录图谱的新方法 (“煽风点火”)。我们将加强对身体共病和行为的描述，包括使用 移动评估体力活动和日常功能，增加生物标志物的使用频率 每18个月评估一次。该项目与NIMH战略目标2：绘制心智图表有关 疾病轨迹以确定何时、何地以及如何干预。展示其存在和 描述深圳生物加速老化的模式将极大地促进对 现实世界的后果、风险因素和潜在机制，这些共同提供了新的方法 预测、跟踪和治疗深圳严重医疗合并症，降低病死率。终极的 目标是改善深圳人的整体健康，延长他们的寿命。

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.