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

项目摘要 端粒长度和端粒酶活性被认为是细胞衰老、长寿和衰老的生物标志物。 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，慢性病的发病率仍然没有得到很好的定义，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很少。的目标 拟研究的是探讨表型和基因型之间的身体组成措施的关系 (e.g.,端粒长度和端粒酶活性，并探讨端粒长度和端粒酶活性的作用， 端粒酶活性与成人代谢危险因素及疾病的关系 使用纵向研究设计，我们建议测量从10岁到12岁的连续白细胞端粒长度（LTL）。 1794个Fels纵向样本中现有储存（n=4204）和新采集（n=1000）的血沉棕黄层样本 研究参与者的年龄范围为18-93岁。费尔斯纵向研究的参与者一再被 测量他们一生的身体成分和代谢指标。随着时间的推移， 使用MRI测量身体组成，如内脏和皮下腹部肥胖，以及新的 还收集了血液化学物质如炎症标记物。全基因组单 在这些参与者的一个大的子集上可以获得核苷酸多态性（SNP）数据以搜索基因 影响端粒生物学。这一独特的有价值的队列提供了一个现成的，具有成本效益的， 了解端粒生物学和心脏代谢健康之间的关系的强大资源。 这项研究的具体目的是：1）检查肥胖与肥胖之间的纵向联系。 特征，端粒长度和代谢风险，2）检查横截面之间的关系， 新收集的端粒酶活性、端粒长度、肥胖特征和代谢危险因素亚组 （N=1000）的参与者，以及3）鉴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查肥胖、端粒生物学和 研究参与者亚组（N=1247）的代谢风险。 这项研究的结果将提供关于端粒生物学如何与 肥胖、衰老和心脏代谢疾病风险。此外，这些信息将有助于评估风险， 预防和治疗加速老化和慢性疾病。

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.