Telomere Length Dynamics in Relation to Changes in Adiposity and Metabolic Risk

项目总结 端粒长度和端粒酶活性已被认为是细胞衰老、长寿和 与年龄相关的疾病，如心血管疾病和2型糖尿病。它们在病理生理学中的作用 然而，慢性病的定义仍然不明确，因为它们也被证明受到 肥胖症。此外，关于遗传学在端粒生物学中的作用的信息也很少。该计划的目标 建议的研究是探索表型和基因型体成分指标之间的关系 (如肥胖)与端粒长度和端粒酶活性的关系，并研究端粒长度和端粒酶活性之间的关系。 端粒酶活性对代谢危险因素和成人疾病的影响。 使用纵向研究设计，我们建议测量序列白细胞端粒长度(LTL)从 1794年FEL纵向已存(n=4204)和新收集(n=1000)浅黄色涂层样本 研究参与者的年龄从18岁到93岁不等。FELS纵向研究参与者反复接受 在他们的一生中测量身体成分和代谢标记物。随着时间的推移，更高级 使用MRI测量身体成分，如内脏和皮下腹脂，以及新的 血液化学指标，如炎症标志物，也已被收集。全基因组单 核苷酸多态(SNP)数据在这些参与者中的一大部分上可用来搜索基因 影响端粒生物学。这一独特的有价值的群体提供了现成的、经济高效的 了解端粒生物学和心脏代谢健康之间关系的强大资源。 这项拟议的研究的具体目的是：1)检查肥胖与肥胖之间的纵向联系 1794名成年人的特征、端粒长度和代谢风险，2)检查横断面关系 一组新收集的端粒酶活性、端粒长度、肥胖特征和代谢危险因素 (n=1000)参与者，以及3)确定影响端粒长度和端粒酶活性的遗传变异 并使用孟德尔随机化来检验肥胖、端粒生物学和 研究参与者子组(N=1247)的代谢风险。 这项拟议的研究结果将提供有关端粒生物学如何与 肥胖、衰老和心脏代谢性疾病的风险。此外，这些信息将有助于风险评估， 防治加速衰老和慢性病。

PROJECT SUMMARY Telomere length and telomerase activity have been posited as biomarkers for cellular aging, longevity, and age-related conditions such as cardiovascular disease and type 2 diabetes. Their role in the pathophysiology of chronic diseases, however, is still not well-defined, as they have been shown to also be influenced by adiposity. Moreover, information on the role of genetics in telomere biology is scarce. The objectives of the proposed study are to explore the phenotypic and genotypic relationship between body composition measures (e.g., obesity) and telomere length and telomerase activity, and to investigate the role of telomere length and telomerase activity on metabolic risk factors and disease in adults. Using a longitudinal study design, we propose to measure serial leukocyte telomere length (LTL) from already existing stored (n=4204) and newly collected (n=1000) buffy coat samples in 1794 Fels Longitudinal Study participants ranging in age from 18-93 years. Fels Longitudinal Study participants have been repeatedly measured over their entire lifetime for body composition and metabolic markers. Over time, more advanced measures of body composition such as visceral and subcutaneous abdominal adiposity using MRI, and novel blood chemistries such as inflammatory markers have been also been collected. Whole genome single nucleotide polymorphism (SNP) data are available on a large subset of these participants to search for genes influencing telomere biology. This uniquely valuable cohort presents a readily available, cost-effective, and powerful resource for understanding the relationship between telomere biology and cardiometabolic health. The specific aims of the proposed study are: 1) to examine longitudinal associations between adiposity traits, telomere length, and metabolic risk in 1794 adults, 2) to examine cross-sectional relationships between newly collected telomerase activity, telomere length, adiposity traits, and metabolic risk factors in a subset (N=1000) of participants, and 3) to identify genetic variants influencing telomere length and telomerase activity and to use Mendelian Randomization to examine causal associations among obesity, telomere biology and metabolic risk in a subset (N=1247) of study participants. The results of this proposed study will provide important information about how telomere biology is linked to obesity, aging, and cardiometabolic disease risk. Further, this information will aid in the assessment of risk, prevention and treatment of accelerated aging and chronic disease.